Sonic Hedgehog信号通路活性下调参与人类肝细胞癌中5-FU抑癌作用的研究
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摘要
当代生物学和医学研究的重要目标之一是增强对肿瘤的治疗效果,最终实现彻底治疗。化疗作为肿瘤治疗的主要手段,其作用机理决定了在发生作用时缺乏选择性,对患者产生全身性的毒副作用,限制了疗效的提高。因而改进治疗方法和开发副作用小的化疗新药等成为科研人员的重要课题。目前有关化疗的研究热点主要有:一、研究和开发特异的小分子化合物或生物活性分子,来特异性激活或关闭癌细胞中与增殖、凋亡和代谢有关的细胞信号通路活性,从而提高化疗药物的特异性,增强疗效。这是提高肿瘤化疗效果的最具希望和最有潜力的途径。二、通过传统化疗药物和新药(包括新开发的具有抑瘤效果的化学药物和天然药物)的相互作用,对患者联合用药,从而增强肿瘤细胞对化疗药物的敏感性(主要是克服肿瘤细胞对化疗药物的耐药性),这是提高肿瘤化疗效果的重要途径。三、通过改善用药方式,使药物通过各种手段直接作用于局部的实体瘤,并且缓慢释放,达到长效抑制肿瘤进而杀死肿瘤细胞的效果。
研究显示,动物胚胎发育过程中的一些信号通路和肿瘤的发生和发展密切相关,如Wnt、Hh、Notch和BMP信号通路等。其中Hh信号通路和肿瘤的关系是近些年的研究热点之一。Hh信号通路不但在细胞命运的决定和组织图式的形成中起到至关重要的作用,而且在肿瘤发生和发展中也起到关键作用。近年来,Hh信号通路在人类肝细胞癌(HCC,Hepatocellular caner)中的作用和意义正逐步为研究者所重视。有研究表明,Sonic Hedgehog(SHh)信号通路在HCC中是高频率激活的,并参与了HCC的发生和发展。因此,HCC中SHh信号通路的有关研究对以细胞信号通路为靶标的特异性治疗策略具有重要价值。但目前为止,有关HCC的研究很少涉及在化疗药物作用下SHh信号通路所发生的变化。
本论文以SHh通路激活的Hep3B细胞为研究材料,重点关注传统化疗药物5-FU对SHh信号通路活性的影响,以及该信号通路的活性改变是否与肝癌细胞的生长和迁移能力有关。
本研究首先用MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide]法确认了以5-FU处理Hep3B细胞系48 h的半数抑制浓度为合适的工作浓度。5-FU作用于Hep3B细胞6 h,12 h,24 h和48 h时,通过半定量RT-PCR检测,发现5-FU可以下调SHh通路靶基因PTC1(Patched 1)和Glil(glioma-associated oncogene homolog 1)、配体基因SHH(Sonic Hedgehog)和受体基因SMO(Smoothened)的表达,表明5-FU对Hep3B细胞中SHh信号通路的主要元件的基因转录有影响。而在SHh通路无活性的HepG2细胞中,没有检测到PTC1和Glil表达,配体SHH也没有受到明显影响。
为确定SHh通路的活性是否参与5-FU引发的生长阻滞和细胞凋亡,本研究通过pCS2-Glil质粒使Hep3B细胞过表达Glil,用MTT检测发现,当施加相同浓度的5-FU时,转染组比非转染组的Hep3B细胞具有更高的生长曲线;台盼蓝染色实验更是直接验证了MTT的检测结果;吖啶橙荧光染色实验发现,除了细胞核发生了明显的凝缩、边缘化和片段化,并有凋亡小体出现外,5-FU处理48h的转染组比非转染组的细胞凋亡比例明显减少;而用Hochest33258的荧光检测,除了发现细胞核在形态上有明显的凋亡特征外,还发现5-FU处理组比对照组的亮度强很多,荧光强度比较显著(*,p＜0.05),而Glil转染组的Hep3B细胞与对照组相比,虽然荧光强度有所增强,但程度不明显;用TUNEL检测以及相应的荧光强度的统计学分析发现,实验中Glil转染组中TUNEL阳染的细胞数量减少,而未转染Glil的实验组中阳染的细胞数量较多,5-FU引发的凋亡更为明显。本研究发现,和对照组以及5-FU处理的非转染组相比,转染组Hep3B细胞中Glil的过表达可以拮抗5-FU引发的细胞生长阻滞和细胞凋亡。使Hep3B细胞过表达Glil,从而上调SHh通路活性上调,可在一定程度上降低Hep3B细胞对5-FU的敏感性,增强Hep3B细胞对5-FU的拮抗作用。
本研究的划痕损伤愈合实验发现,使Hep3B细胞过表达Glil可以拯救5-FU引起的迁移能力的降低,表明在SHh通路激活的肿瘤细胞中5-FU对细胞迁移能力的影响可能涉及对通路活性的抑制。
进一步研究发现,过表达Glil的Hep3B细胞可以拮抗5-FU引发的PTC1蛋白亚细胞定位的改变。本研究用荧光免疫细胞化学检测法(ICC,Immunocytochemistry)对Hep3B细胞中PTC1蛋白的亚细胞定位的变化进行了检测,发现当用5-FU处理一定时间后,大多数PTC1蛋白分子失去了它们在膜上的定位,并在细胞质中散乱分布;随着5-FU作用时间的延长和细胞凋亡的进展,PTC1的信号越来越弱,分布也越来越散乱;5-FU处理48 h后,可观察到PTC1蛋白的表达基本消失,这个结果与前面Western Blot的结果是一致的。而使Hep3B细胞过表达Glil可以拮抗5-FU对PTC1蛋白亚细胞定位的改变。实验中还意外地发现PTC1在细胞有丝分裂期的独特分布形式,即分裂末期,胞内的PTC1蛋白似乎离开了它们在核膜附近的定位,大部分被募集到细胞膜上;尤其是在赤道板附近的即将内陷形成两个子细胞的膜区域,PTC1大量表达,暗示了PTC1可能参与有丝分裂过程的调控。
本研究还对G1期晚期的细胞周期蛋白——cyclin E的表达进行了免疫细胞化学检测,发现5-FU作用于Hep3B细胞会引起cyclin E的显著下调;而在转染Glil的Hep3B细胞中,过表达的Glil可以抑制5-FU对cyclin E的下调。因此,过表达的Glil可以部分地抑制5-FU对Hep3B细胞的细胞周期阻滞作用。
综上所述,本研究首次报道了5-FU引起的Hep3B细胞凋亡和迁移能力的抑制涉及SHh信号通路。使Hep3B细胞过表达Glil可以拮抗5-FU对Hep3B细胞的生长阻滞和细胞凋亡效应,拯救5-FU引起的Hep3B细胞的迁移能力的抑制、SHh信号通路受体PTC1的下调和分布变化以及细胞周期蛋白cyclin E的下调。此外,还意外发现在有丝分裂末期PTC1蛋白的分布特点,暗示了PTC1可能参与有丝分裂过程的调控。本研究为基于5-FU的治疗提供了新的治疗策略,即对于SHh信号通路激活的肝细胞癌患者,SHh信号通路抑制剂和化疗药物联合用药可能会代表一种更有前途的HCC治疗方法。这一结果为将来的治疗策略提供了新线索,而且可能在临床应用上具有重要意义。但仍需要进一步利用其他HCC细胞系研究以及进行体内研究。
此外,本论文还研究了一种新的化疗试剂——四唑紫罗兰和传统的亚硝脲类化疗药物——盐酸尼莫斯汀(ACNU)的联合用药能引起化疗增效的现象。
促使化疗增效的重要途径之一是提高肿瘤对传统临床化疗药物(如ACNU等)的敏感性,这已成为研究人员的重要课题。针对化疗药物不同的作用机制,增加肿瘤对化疗药物的敏感性的方式也不尽相同,但其目的都是为了提高化疗药物对肿瘤细胞的杀伤效果、减少对正常细胞的毒性。由于化疗药物的研究深度和选择范围有限,目前所采取的主要方式是通过药物联合作用来逆转各种的耐药机制。TV是一种能引发肿瘤细胞发生G1期阻滞和凋亡的四唑盐类化合物,近年来的研究表明,它可以和氮芥类烷化剂——BCNU联合作用,增加肿瘤细胞对卡氮芥的敏感性,因此是一种有希望的化疗试剂。然而TV和亚硝脲类烷化剂——ACNU的联合化疗,在治疗脑胶质瘤中是否起到增效作用,从而改善对脑胶质瘤联合化疗的疗效,目前尚未研究。因此,在较为理想的哺乳动物脑胶质瘤的体外模型——C6大鼠脑胶质瘤细胞中,本研究对TV和ACNU联合用药起到的增效作用及其可能的增效机制进行了研究,这可能对脑胶质瘤的联合化疗具有一定的意义。
本研究表明,ACNU和TV联合用药可以提高每种药物单用对C6细胞的增殖抑制作用,促进细胞凋亡,起到增效作用;同时,这种增效作用会引起野生型p53蛋白,以及细胞周期相关蛋白p21、p27的显著上调;而且通过检测耐药相关蛋白——GSTs的酶活水平,本研究发现它和增效作用的相关性不高。因此,联合用药的增效机制仍将需要进一步深入探讨。
由于本研究所涉及的对脑胶质瘤联合化疗的增效作用是一个多种因素参与的复杂过程,单方面考虑某一基因或蛋白的作用很难充分解释化疗中遇到的实际情况。因此,对脑胶质瘤的研究必须多基因、多途径地寻找其耐药机制,以逆转其耐药,增强化疗疗效。
总之,本研究的两部分为提高化疗效果的基础性研究拓展了研究领域。虽然两部分的详细机制仍待探讨,但这些实验数据为深入研究肿瘤化疗作用机制及丰富化疗手段提供了有益的线索。
创新点:
首次报道了5-FU引起的Hep3B细胞凋亡和迁移能力的抑制涉及SHH信号通路活性的下调,为将来结合细胞信号通路改变的化疗增效提供思路;
首次报道了TV和ACNU药物联用起到化疗增效作用,为临床上联合用药提供新的线索。
To increase the therapeutic efficacy for tumors so as to achieve thorough therapy finally is one of essential targets of current biology and medical science.As one of the main approaches to tumor treatment,chemotherapy itself had some defaults which are determined by the mechanisms of chemotherapeutic agents themselvees, such as the deficiency of selectivity and general deleterious side effect for patients. Thus,the therapeutic efficacies are limited.The improvement of therapeutic methods and the exploration of new chemotherapeutic agents little side effect have been an essential task for researchers.The hot topics about current chemotherapy include following:one,to elevate the specificity and chemotherapeutic efficacy through switching on or off the activity of cell signaling pathway related to proliferation, apoptosis and metabolism by investigating and developing specific small compounds or molecules with biological activities,which is the most promising and potential approaches;two,to sensitize the tumor cells to chemicals(mainly through overcoming the drug-resistance of cells) by means of combination chemotherapy of traditional chemotherapeutic agents and new drugs(including newly-developed chemicals and natural drugs that had inhibitive effect of tumors),which is an important approach for better chemotherapeutic efficacy;three,to amend the medication ways by various means of targeting topical solid tumors directly and releasing slowly in order to inhibit tumors longer and kill the tumor cells.
It is shown that some of signaling pathway of animal embryonic development correlated closely with tumorigenesis and tumor development,such as Wnt,Hh, Notch,BMP signaling pathways,etc.The relationship between Hh signaling pathway and tumors is one of hot spots in research in recent years.Hh signaling pathway is not only extremely important for the patterning and cell fate decision,but also crucial in tumorigenesis and tumor development.Recently,the role and significance of Hh signaling in human hepatocellular cancer(HCC) is highlighted by and by.It is demonstrated that SHh(Sonic Hedgehog) signaling pathway is frequently activated in HCC and participate in carcinogenesis and development of HCC.Thus,the correlated research on Hh signaling pathway has essential values in specific treatment strategy targeted by cell signaling pathway.By far,the research on HCC seldom involved the alteration of SHh signaling pathway with chemotherapeutic treatment.
The research materials in present dissertation is based on Hep3B cells which has activated SHh signaling pathway,and what we cared is whether the alterations of Hh signaling activity has relationship with the growth and migration ability of HCC cells.
The present study confirmed proper work concentration by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]assay,which is 50% inhibition concentration for Hep3B cells treated for 48 h.When treatment elapsed by 6 h,12 h,24 h and 48 h,the results from semi-quantitative RT-PCR found the down regulation of target genes PTC1(Patched 1) and Gli1(glioma-associated oncogene homolog 1),ligand gene SHH(Sonic Hedgehog) and receptor gene SMO (Smoothened),indicated the influence of 5-FU on main components in SHh signaling pathway.While in the case of HepG2 cells,there is no expression of PTC1 and Gli1,and the expression of SHH ligand was not affected obviously.
To confirm whether the cell growth arrest and apoptosis induced by 5-FU involves the activity of SHh signaling pathway,the present study made Gli1 overexpressed in Hep3B cells and when exposed to the same concentration of 5-FU, the transfection groups had higher survival curve than non-transfection groups in MTT assay.The results in MTT assay was also demonstrated directly by Trypan Blue assay;it is observed under fluorescent microscope in acridine dyeing assay that the nuclei in part of Hep3B cells happened to be of gragmentation,marginalization and chromatic agglutination with apoptotic body scattered around,and besides these, it was found that 5-FU treated transfection groups at 48 h had significant decrease comparing with non-transfection groups.As for Hochest33258 fluorescent assay, except for obvious apoptotic characteristics of nuclei,we found the average fluorescent intensity in 5-FU treated groups was much stronger than control groups (~*,p＜0.05),while the average fluorescent intensity in transfection groups is also stronger than that in control groups,but with no significant difference.TUNEL assay and corresponding fluorescent intensity assay with statistical analysis showed remarkable decrease trend in transfection groups with 5-FU treated,comparing with non-transfection groups with 5-FU treated.So,in present study the overexpression of Gli1 in trasfection group was found to antagonize the cell growth arrest and apoptosis induced by 5-FU.The overexpression of Gli1 in Hep3B cells can also elevate the activity of SHh signaling pathway,thus it decreased the sensitivity of Hep3B cells with 5-FU treatment and increased antagonistic effect in Hep3B cells.
Our study found through scratch wound closure assay showed that the overexpression of Gli1 can rescue the decrease in motility of Hep3B cells induced by 5-FU,and this indicated that 5-FU may have influenced motility of SHh-activated tumor cells,which is involved inhibition of the activity of pathway.
Besides,the overexpression of Gli1 in Hep3B cells may antagonize the change of subcellular location of PTC1.In this study,we detected the subcellular location of PTC1 in Hep3B cells through immunocytochemistry(ICC) assay,and found most of the PTC1 lost their location on membrane and distributed dispersedly with 5-FU treated for certain period.With time passed by and apoptosis progression,the signal from PTC1 became weaker and distribution became more scattered.After the treatment for 48 h,the expression of PTC1 was almost disappeared,this is consistent with the results in Western Blot.What's more,the overexpression of Gli1 may antagonize the alteration of subcellular location for PTC1 in Hep3B cells treated with 5-FU.Unexpectedly,the unique intracellular distribution of PTC1 in telophase of mitosis was found in our study,which possibly meant the isolation of PTC1 from their location near nuclear envelope and the recruitment of a major of PTC1 on cell membrane.Especially,near the equatorial plate region where the membrane was going to invaginate to form daughter cells,PTC1 was expressed in large amount,and this implies that PTC1 may involve the regulation of mitosis.
Furthermore,the study detected the expression of cyclin E,the cyclin that can function in late G1 phase,in ICC assay.We found significant down regulation of cyclin E induced by 5-FU in Hep3B cells.While in transfection groups,the overexpression of Gli1 in Hep3B cells can inhibit the down regulation of cyclin E. Thus,the overexpression of Gli1 may partially inhibit the cell growth arrest of Hep3B.
In conclusion,our study for the first time reported that down-regulation of SHh signaling pathway activity is involved in 5-fluorouracil-induced apoptosis and motility inhibition in Hep3B cells.The overexpression of Gli1 can antagonize the effect of the cell growth arrest and apoptosis,and can also rescue motility inhibition of Hep3B cells induced by 5-FU,down regulation of receptor PTC1 with distribution change and cell cycle related protein,cyclin E.Besides,we found a unique distribution character of PTC1 at telophase in mitosis unexpectedly,which implies its involvement in regulation of mitosis.The study provides a new therapeutic strategy for 5-FU based therapy.As for HCC patients with SHh signaling pathway activated,the combination of inhibitor of SHh signaling pathway and other chemotherapeutic agents may represent a more promising therapy for HCC patients.
In addition,the study made the research on combination chemotherapy of a new chemical,TV(tetrazolium violet) and traditional nitrosourea chemotherapeutic agents,ACNU(nimustine hydrochloride),which can cause synergistic effect in combination chemotherapy.
One of important ways to promote synergy in chemotherapy is to increase the sensitivity of therapeutic agents,especially for traditional clinical drugs,such as ACNU.And this have become to important topics for researchers.Targeting to different mechanisms of chemotherapeutic agents,researchers have increased the sensitivity of different therapeutic agents with different ways,but all the destinations are to increase the chemotherapeutic effect of drugs or decrease their deleterious effect to normal cells.For the sake of limited research depth and selective range,in present,the common way to reverse various possible drug-resistance mechanisms is combination chemotherapy.TV is a tetrazolium salts that can elicit cell growth arrest at G1 phase and apoptosis for tumor cells.Recent research indicated that TV can cooperate with BCNU(carmustine) to elevate the sensitivity of tumor ceils to BCNU. Therefore,TV is a promising chemotherapeutic agent.But whether the combination chemotherapy of ACNU and TV can cause synergy in treatment for gliomas,and whether this combination chemotherapeutic approaches for gliomas will be improved is unknown.Thus,we perform the tests on C6 rat glioma cells which is an ideal model in vitro for gliomas in mammals and we investigate the synergistic effect of this combination chemotherapy and possible synergistic mechanism,which may have essential significancy in therapy in gliomas.
The present study indicated that the combination chemotherapy of ACNU and TV can promote proliferative inhibition of in C6 cells and promote apoptosis, comparing with treatment in single drug;at the same time,this combination chemotherapy will cause up regulation in wild type p53 protein,cell cycle related protein p21 and p27;furthermore,we measured the activity of drug-resistant protein, only to find little relevance.Thus,the synergistic mechanism of this combination needs further tests and other analysis in future.
Since the synergistic effect of combination chemotherapy for gliomas is a complicated process with multiple factors,it is hard to elucidate the practical problems with the function of only one gene or one protein.Thus,the research on gliomas must seek the drug-resistant mechanisms from multiple genes and approaches in order to reverse the drug-resistance and improve the chemotherapeutic efficacy.
On the whole,the two parts of this study improved basic research on chemotherapeutic efficacy and expand the investigation field.Although the specific mechanisms is yet required to further investigation,these data provide the helpful clues to further investigation on chemotherapeutic mechanism of action,and to enrich the chemotherapeutic approaches.
Innovations:
To report for the first time that down-regulation of SHh signaling pathway activity is involved in 5-fluorouracil-induced apoptosis and motility inhibition in Hep3B cells,which provides new clues to chemotherapeutic synergy in future, combined with alterations of cell signaling pathways.
To report for the first time that combination chemotherapeutic of TV and ACNU will bring about synergistic effect on C6 cells,which will provide effective scheme to combination chemotherapy clinically.
研究显示,动物胚胎发育过程中的一些信号通路和肿瘤的发生和发展密切相关,如Wnt、Hh、Notch和BMP信号通路等。其中Hh信号通路和肿瘤的关系是近些年的研究热点之一。Hh信号通路不但在细胞命运的决定和组织图式的形成中起到至关重要的作用,而且在肿瘤发生和发展中也起到关键作用。近年来,Hh信号通路在人类肝细胞癌(HCC,Hepatocellular caner)中的作用和意义正逐步为研究者所重视。有研究表明,Sonic Hedgehog(SHh)信号通路在HCC中是高频率激活的,并参与了HCC的发生和发展。因此,HCC中SHh信号通路的有关研究对以细胞信号通路为靶标的特异性治疗策略具有重要价值。但目前为止,有关HCC的研究很少涉及在化疗药物作用下SHh信号通路所发生的变化。
本论文以SHh通路激活的Hep3B细胞为研究材料,重点关注传统化疗药物5-FU对SHh信号通路活性的影响,以及该信号通路的活性改变是否与肝癌细胞的生长和迁移能力有关。
本研究首先用MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide]法确认了以5-FU处理Hep3B细胞系48 h的半数抑制浓度为合适的工作浓度。5-FU作用于Hep3B细胞6 h,12 h,24 h和48 h时,通过半定量RT-PCR检测,发现5-FU可以下调SHh通路靶基因PTC1(Patched 1)和Glil(glioma-associated oncogene homolog 1)、配体基因SHH(Sonic Hedgehog)和受体基因SMO(Smoothened)的表达,表明5-FU对Hep3B细胞中SHh信号通路的主要元件的基因转录有影响。而在SHh通路无活性的HepG2细胞中,没有检测到PTC1和Glil表达,配体SHH也没有受到明显影响。
为确定SHh通路的活性是否参与5-FU引发的生长阻滞和细胞凋亡,本研究通过pCS2-Glil质粒使Hep3B细胞过表达Glil,用MTT检测发现,当施加相同浓度的5-FU时,转染组比非转染组的Hep3B细胞具有更高的生长曲线;台盼蓝染色实验更是直接验证了MTT的检测结果;吖啶橙荧光染色实验发现,除了细胞核发生了明显的凝缩、边缘化和片段化,并有凋亡小体出现外,5-FU处理48h的转染组比非转染组的细胞凋亡比例明显减少;而用Hochest33258的荧光检测,除了发现细胞核在形态上有明显的凋亡特征外,还发现5-FU处理组比对照组的亮度强很多,荧光强度比较显著(*,p＜0.05),而Glil转染组的Hep3B细胞与对照组相比,虽然荧光强度有所增强,但程度不明显;用TUNEL检测以及相应的荧光强度的统计学分析发现,实验中Glil转染组中TUNEL阳染的细胞数量减少,而未转染Glil的实验组中阳染的细胞数量较多,5-FU引发的凋亡更为明显。本研究发现,和对照组以及5-FU处理的非转染组相比,转染组Hep3B细胞中Glil的过表达可以拮抗5-FU引发的细胞生长阻滞和细胞凋亡。使Hep3B细胞过表达Glil,从而上调SHh通路活性上调,可在一定程度上降低Hep3B细胞对5-FU的敏感性,增强Hep3B细胞对5-FU的拮抗作用。
本研究的划痕损伤愈合实验发现,使Hep3B细胞过表达Glil可以拯救5-FU引起的迁移能力的降低,表明在SHh通路激活的肿瘤细胞中5-FU对细胞迁移能力的影响可能涉及对通路活性的抑制。
进一步研究发现,过表达Glil的Hep3B细胞可以拮抗5-FU引发的PTC1蛋白亚细胞定位的改变。本研究用荧光免疫细胞化学检测法(ICC,Immunocytochemistry)对Hep3B细胞中PTC1蛋白的亚细胞定位的变化进行了检测,发现当用5-FU处理一定时间后,大多数PTC1蛋白分子失去了它们在膜上的定位,并在细胞质中散乱分布;随着5-FU作用时间的延长和细胞凋亡的进展,PTC1的信号越来越弱,分布也越来越散乱;5-FU处理48 h后,可观察到PTC1蛋白的表达基本消失,这个结果与前面Western Blot的结果是一致的。而使Hep3B细胞过表达Glil可以拮抗5-FU对PTC1蛋白亚细胞定位的改变。实验中还意外地发现PTC1在细胞有丝分裂期的独特分布形式,即分裂末期,胞内的PTC1蛋白似乎离开了它们在核膜附近的定位,大部分被募集到细胞膜上;尤其是在赤道板附近的即将内陷形成两个子细胞的膜区域,PTC1大量表达,暗示了PTC1可能参与有丝分裂过程的调控。
本研究还对G1期晚期的细胞周期蛋白——cyclin E的表达进行了免疫细胞化学检测,发现5-FU作用于Hep3B细胞会引起cyclin E的显著下调;而在转染Glil的Hep3B细胞中,过表达的Glil可以抑制5-FU对cyclin E的下调。因此,过表达的Glil可以部分地抑制5-FU对Hep3B细胞的细胞周期阻滞作用。
综上所述,本研究首次报道了5-FU引起的Hep3B细胞凋亡和迁移能力的抑制涉及SHh信号通路。使Hep3B细胞过表达Glil可以拮抗5-FU对Hep3B细胞的生长阻滞和细胞凋亡效应,拯救5-FU引起的Hep3B细胞的迁移能力的抑制、SHh信号通路受体PTC1的下调和分布变化以及细胞周期蛋白cyclin E的下调。此外,还意外发现在有丝分裂末期PTC1蛋白的分布特点,暗示了PTC1可能参与有丝分裂过程的调控。本研究为基于5-FU的治疗提供了新的治疗策略,即对于SHh信号通路激活的肝细胞癌患者,SHh信号通路抑制剂和化疗药物联合用药可能会代表一种更有前途的HCC治疗方法。这一结果为将来的治疗策略提供了新线索,而且可能在临床应用上具有重要意义。但仍需要进一步利用其他HCC细胞系研究以及进行体内研究。
此外,本论文还研究了一种新的化疗试剂——四唑紫罗兰和传统的亚硝脲类化疗药物——盐酸尼莫斯汀(ACNU)的联合用药能引起化疗增效的现象。
促使化疗增效的重要途径之一是提高肿瘤对传统临床化疗药物(如ACNU等)的敏感性,这已成为研究人员的重要课题。针对化疗药物不同的作用机制,增加肿瘤对化疗药物的敏感性的方式也不尽相同,但其目的都是为了提高化疗药物对肿瘤细胞的杀伤效果、减少对正常细胞的毒性。由于化疗药物的研究深度和选择范围有限,目前所采取的主要方式是通过药物联合作用来逆转各种的耐药机制。TV是一种能引发肿瘤细胞发生G1期阻滞和凋亡的四唑盐类化合物,近年来的研究表明,它可以和氮芥类烷化剂——BCNU联合作用,增加肿瘤细胞对卡氮芥的敏感性,因此是一种有希望的化疗试剂。然而TV和亚硝脲类烷化剂——ACNU的联合化疗,在治疗脑胶质瘤中是否起到增效作用,从而改善对脑胶质瘤联合化疗的疗效,目前尚未研究。因此,在较为理想的哺乳动物脑胶质瘤的体外模型——C6大鼠脑胶质瘤细胞中,本研究对TV和ACNU联合用药起到的增效作用及其可能的增效机制进行了研究,这可能对脑胶质瘤的联合化疗具有一定的意义。
本研究表明,ACNU和TV联合用药可以提高每种药物单用对C6细胞的增殖抑制作用,促进细胞凋亡,起到增效作用;同时,这种增效作用会引起野生型p53蛋白,以及细胞周期相关蛋白p21、p27的显著上调;而且通过检测耐药相关蛋白——GSTs的酶活水平,本研究发现它和增效作用的相关性不高。因此,联合用药的增效机制仍将需要进一步深入探讨。
由于本研究所涉及的对脑胶质瘤联合化疗的增效作用是一个多种因素参与的复杂过程,单方面考虑某一基因或蛋白的作用很难充分解释化疗中遇到的实际情况。因此,对脑胶质瘤的研究必须多基因、多途径地寻找其耐药机制,以逆转其耐药,增强化疗疗效。
总之,本研究的两部分为提高化疗效果的基础性研究拓展了研究领域。虽然两部分的详细机制仍待探讨,但这些实验数据为深入研究肿瘤化疗作用机制及丰富化疗手段提供了有益的线索。
创新点:
首次报道了5-FU引起的Hep3B细胞凋亡和迁移能力的抑制涉及SHH信号通路活性的下调,为将来结合细胞信号通路改变的化疗增效提供思路;
首次报道了TV和ACNU药物联用起到化疗增效作用,为临床上联合用药提供新的线索。
To increase the therapeutic efficacy for tumors so as to achieve thorough therapy finally is one of essential targets of current biology and medical science.As one of the main approaches to tumor treatment,chemotherapy itself had some defaults which are determined by the mechanisms of chemotherapeutic agents themselvees, such as the deficiency of selectivity and general deleterious side effect for patients. Thus,the therapeutic efficacies are limited.The improvement of therapeutic methods and the exploration of new chemotherapeutic agents little side effect have been an essential task for researchers.The hot topics about current chemotherapy include following:one,to elevate the specificity and chemotherapeutic efficacy through switching on or off the activity of cell signaling pathway related to proliferation, apoptosis and metabolism by investigating and developing specific small compounds or molecules with biological activities,which is the most promising and potential approaches;two,to sensitize the tumor cells to chemicals(mainly through overcoming the drug-resistance of cells) by means of combination chemotherapy of traditional chemotherapeutic agents and new drugs(including newly-developed chemicals and natural drugs that had inhibitive effect of tumors),which is an important approach for better chemotherapeutic efficacy;three,to amend the medication ways by various means of targeting topical solid tumors directly and releasing slowly in order to inhibit tumors longer and kill the tumor cells.
It is shown that some of signaling pathway of animal embryonic development correlated closely with tumorigenesis and tumor development,such as Wnt,Hh, Notch,BMP signaling pathways,etc.The relationship between Hh signaling pathway and tumors is one of hot spots in research in recent years.Hh signaling pathway is not only extremely important for the patterning and cell fate decision,but also crucial in tumorigenesis and tumor development.Recently,the role and significance of Hh signaling in human hepatocellular cancer(HCC) is highlighted by and by.It is demonstrated that SHh(Sonic Hedgehog) signaling pathway is frequently activated in HCC and participate in carcinogenesis and development of HCC.Thus,the correlated research on Hh signaling pathway has essential values in specific treatment strategy targeted by cell signaling pathway.By far,the research on HCC seldom involved the alteration of SHh signaling pathway with chemotherapeutic treatment.
The research materials in present dissertation is based on Hep3B cells which has activated SHh signaling pathway,and what we cared is whether the alterations of Hh signaling activity has relationship with the growth and migration ability of HCC cells.
The present study confirmed proper work concentration by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]assay,which is 50% inhibition concentration for Hep3B cells treated for 48 h.When treatment elapsed by 6 h,12 h,24 h and 48 h,the results from semi-quantitative RT-PCR found the down regulation of target genes PTC1(Patched 1) and Gli1(glioma-associated oncogene homolog 1),ligand gene SHH(Sonic Hedgehog) and receptor gene SMO (Smoothened),indicated the influence of 5-FU on main components in SHh signaling pathway.While in the case of HepG2 cells,there is no expression of PTC1 and Gli1,and the expression of SHH ligand was not affected obviously.
To confirm whether the cell growth arrest and apoptosis induced by 5-FU involves the activity of SHh signaling pathway,the present study made Gli1 overexpressed in Hep3B cells and when exposed to the same concentration of 5-FU, the transfection groups had higher survival curve than non-transfection groups in MTT assay.The results in MTT assay was also demonstrated directly by Trypan Blue assay;it is observed under fluorescent microscope in acridine dyeing assay that the nuclei in part of Hep3B cells happened to be of gragmentation,marginalization and chromatic agglutination with apoptotic body scattered around,and besides these, it was found that 5-FU treated transfection groups at 48 h had significant decrease comparing with non-transfection groups.As for Hochest33258 fluorescent assay, except for obvious apoptotic characteristics of nuclei,we found the average fluorescent intensity in 5-FU treated groups was much stronger than control groups (~*,p＜0.05),while the average fluorescent intensity in transfection groups is also stronger than that in control groups,but with no significant difference.TUNEL assay and corresponding fluorescent intensity assay with statistical analysis showed remarkable decrease trend in transfection groups with 5-FU treated,comparing with non-transfection groups with 5-FU treated.So,in present study the overexpression of Gli1 in trasfection group was found to antagonize the cell growth arrest and apoptosis induced by 5-FU.The overexpression of Gli1 in Hep3B cells can also elevate the activity of SHh signaling pathway,thus it decreased the sensitivity of Hep3B cells with 5-FU treatment and increased antagonistic effect in Hep3B cells.
Our study found through scratch wound closure assay showed that the overexpression of Gli1 can rescue the decrease in motility of Hep3B cells induced by 5-FU,and this indicated that 5-FU may have influenced motility of SHh-activated tumor cells,which is involved inhibition of the activity of pathway.
Besides,the overexpression of Gli1 in Hep3B cells may antagonize the change of subcellular location of PTC1.In this study,we detected the subcellular location of PTC1 in Hep3B cells through immunocytochemistry(ICC) assay,and found most of the PTC1 lost their location on membrane and distributed dispersedly with 5-FU treated for certain period.With time passed by and apoptosis progression,the signal from PTC1 became weaker and distribution became more scattered.After the treatment for 48 h,the expression of PTC1 was almost disappeared,this is consistent with the results in Western Blot.What's more,the overexpression of Gli1 may antagonize the alteration of subcellular location for PTC1 in Hep3B cells treated with 5-FU.Unexpectedly,the unique intracellular distribution of PTC1 in telophase of mitosis was found in our study,which possibly meant the isolation of PTC1 from their location near nuclear envelope and the recruitment of a major of PTC1 on cell membrane.Especially,near the equatorial plate region where the membrane was going to invaginate to form daughter cells,PTC1 was expressed in large amount,and this implies that PTC1 may involve the regulation of mitosis.
Furthermore,the study detected the expression of cyclin E,the cyclin that can function in late G1 phase,in ICC assay.We found significant down regulation of cyclin E induced by 5-FU in Hep3B cells.While in transfection groups,the overexpression of Gli1 in Hep3B cells can inhibit the down regulation of cyclin E. Thus,the overexpression of Gli1 may partially inhibit the cell growth arrest of Hep3B.
In conclusion,our study for the first time reported that down-regulation of SHh signaling pathway activity is involved in 5-fluorouracil-induced apoptosis and motility inhibition in Hep3B cells.The overexpression of Gli1 can antagonize the effect of the cell growth arrest and apoptosis,and can also rescue motility inhibition of Hep3B cells induced by 5-FU,down regulation of receptor PTC1 with distribution change and cell cycle related protein,cyclin E.Besides,we found a unique distribution character of PTC1 at telophase in mitosis unexpectedly,which implies its involvement in regulation of mitosis.The study provides a new therapeutic strategy for 5-FU based therapy.As for HCC patients with SHh signaling pathway activated,the combination of inhibitor of SHh signaling pathway and other chemotherapeutic agents may represent a more promising therapy for HCC patients.
In addition,the study made the research on combination chemotherapy of a new chemical,TV(tetrazolium violet) and traditional nitrosourea chemotherapeutic agents,ACNU(nimustine hydrochloride),which can cause synergistic effect in combination chemotherapy.
One of important ways to promote synergy in chemotherapy is to increase the sensitivity of therapeutic agents,especially for traditional clinical drugs,such as ACNU.And this have become to important topics for researchers.Targeting to different mechanisms of chemotherapeutic agents,researchers have increased the sensitivity of different therapeutic agents with different ways,but all the destinations are to increase the chemotherapeutic effect of drugs or decrease their deleterious effect to normal cells.For the sake of limited research depth and selective range,in present,the common way to reverse various possible drug-resistance mechanisms is combination chemotherapy.TV is a tetrazolium salts that can elicit cell growth arrest at G1 phase and apoptosis for tumor cells.Recent research indicated that TV can cooperate with BCNU(carmustine) to elevate the sensitivity of tumor ceils to BCNU. Therefore,TV is a promising chemotherapeutic agent.But whether the combination chemotherapy of ACNU and TV can cause synergy in treatment for gliomas,and whether this combination chemotherapeutic approaches for gliomas will be improved is unknown.Thus,we perform the tests on C6 rat glioma cells which is an ideal model in vitro for gliomas in mammals and we investigate the synergistic effect of this combination chemotherapy and possible synergistic mechanism,which may have essential significancy in therapy in gliomas.
The present study indicated that the combination chemotherapy of ACNU and TV can promote proliferative inhibition of in C6 cells and promote apoptosis, comparing with treatment in single drug;at the same time,this combination chemotherapy will cause up regulation in wild type p53 protein,cell cycle related protein p21 and p27;furthermore,we measured the activity of drug-resistant protein, only to find little relevance.Thus,the synergistic mechanism of this combination needs further tests and other analysis in future.
Since the synergistic effect of combination chemotherapy for gliomas is a complicated process with multiple factors,it is hard to elucidate the practical problems with the function of only one gene or one protein.Thus,the research on gliomas must seek the drug-resistant mechanisms from multiple genes and approaches in order to reverse the drug-resistance and improve the chemotherapeutic efficacy.
On the whole,the two parts of this study improved basic research on chemotherapeutic efficacy and expand the investigation field.Although the specific mechanisms is yet required to further investigation,these data provide the helpful clues to further investigation on chemotherapeutic mechanism of action,and to enrich the chemotherapeutic approaches.
Innovations:
To report for the first time that down-regulation of SHh signaling pathway activity is involved in 5-fluorouracil-induced apoptosis and motility inhibition in Hep3B cells,which provides new clues to chemotherapeutic synergy in future, combined with alterations of cell signaling pathways.
To report for the first time that combination chemotherapeutic of TV and ACNU will bring about synergistic effect on C6 cells,which will provide effective scheme to combination chemotherapy clinically.
引文
Abe,Y.,E.Oda-Sato,et al.(2008)."Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2." Proc Natl Acad Sci U S A 105(12):4838-43.
Adams,J.M.and S.Cory(2001)."Life-or-death decisions by the Bcl-2 protein family." Trends Biochem Sci 26(1):61-6.
Agouni,A.,H.A.Mostefai,et al.(2007)."Sonic hedgehog carried by microparticles corrects endothelial injury through nitric oxide release." FASEB J 21(11):2735-41.
Alberts,D.S.,D.Garcia-Kendall,et al.(1988)."Phase Ⅱ trial of mitomycin C plus 5-FU in the treatment of drug-refractory ovarian cancer." Semin Oncol 15(3 Suppl 4):22-6.
Arai,Y.,C.Kido,et al.(1987)."[Preliminary results of a phase Ⅱ study of 5-FU,adriamycin,and mitomycin C(FAM) in combined hepatic infusion in patients with non-resectable metastatic liver cancer]." Gan To Kagaku Ryoho 14(7):2327-33.
Arango,D.,G.A.Corner,et al.(2001)."c-myc/p53 interaction determines sensitivity of human colon carcinoma cells to 5-fluorouracil in vitro and in vivo." Cancer Res 61(12):4910-5.
Arteaga,C.L.(2006)."Inhibition of TGFbeta signaling in cancer therapy." Curt Opin Genet Dev 16(1):30-7.
Asai,J.,H.Takenaka,et al.(2006)."Topical sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling."Circulation 113(20):2413-24.
Athar,M.,C.Li,et al.(2004)."Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis." Cancer Res 64(20):7545-52.
Bai,C.B.,W.Auerbach,et al.(2002)."Gli2,but not Gli1,is required for initial Shh signaling and ectopic activation of the Shh pathway." Development 129(20):4753-61.
Bai,C.B.,D.Stephen,et al.(2004)."All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3." Dev Cell 6(1):103-15.
Baron,M.(2001)."Induction of embryonic hematopoietic and endothelial stem/progenitor cells by hedgehog-mediated signals." Differentiation 68(4-5):175-85.
Beachy,P.A.,S.S.Karhadkar,et al.(2004)."Tissue repair and stem cell renewal in carcinogenesis." Nature 432(7015):324-31.
Bellusci,S.,Y.Furuta,et al.(1997)."Involvement of Sonic hedgehog(Shh) in mouse embryonic lung growth and morphogenesis." Development 124(1):53 -63.
Berman,D.M.,S.S.Karhadkar,et al.(2002)."Medulloblastoma growth inhibition by hedgehog pathway blockade." Science 297(5586):1559-61.
Berman,D.M.,S.S.Karhadkar,et al.(2003)."Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours." Nature 425(6960):846-51.
Bezard,E.,J.Baufreton,et al.(2003)."Sonic hedgehog is a neuromodulator in the adult subthalamic nucleus." FASEB J 17(15):2337-8.
Bigelow,R.L.,N.S.Chari,et al.(2004)."Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1." J Biol Chem 279(2):1197-205.
Bijlsma,M.F.,C.A.Spek,et al.(2006)."Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion." PLoS Biol 4(8):e232.
Blotta,S.and J.Negri(2007)."Hedgehog Pathway as a Potential Therapeutic Target in Multiple Myeloma." Blood(ASH Annual Meeting Abstracts) 110:672.
Bruix,J.,L.Boix,et al.(2004)."Focus on hepatocellular carcinoma." Cancer Cell 5(3):215-9.
Bryden,M.M.,H.E.Evans,et al.(1971)."Cyclopia in sheep caused by plant teratogens." J Anat 110(Pt 3):507.
Budhu,A.and X.W.Wang(2006)."The role of cytokines in hepatocellular carcinoma." J Leukoc Biol 80(6):1197-213.
Calcutt,N.A.,K.L.Allendoerfer,et al.(2003)."Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy." J Clin Invest 111(4):507-14.
Calvisi,D.F.and S.S.Thorgeirsson(2005)."Molecular mechanisms of hepatocarcinogenesis in transgenic mouse models of liver cancer." Toxicol Pathol 33(1):181-4.
Cao,Y.,J.Zhao,et al.(2003)."Expression of zebrafish Lc3 synthase gene in embryonic lens requires hedgehog signaling." Dev Dyn 228(3):308-12.
Caricasole,A.,A.Bakker,et al.(2005)."Two sides of the same coin:Wnt signaling in neurodegeneration and neuro-oncology." Biosci Rep 25(5-6):309-27.
Carlberger,G.and I.Ljungdahl(1971)."[5-FU excretion in anticarcinogenic therapy in liver cancer]."Nord Med 86(46):1360.
Cebra-Thomas,J.A.,J.Bromer,et al.(2003)."T-box gene products are required for mesenchymal induction of epithelial branching in the embryonic mouse lung." Dev Dyn 226(1):82-90.
Chan,C.F.,T.O.Yau,et al.(2004)."Evaluation of nuclear factor-kappaB,urokinase-type plasminogen activator,and HBχ and their clinicopathological significance in hepatocellular carcinoma." Clin Cancer Res 10(12 Pt 1):4140-9.
Chari,N.S.and T.J.McDonnell(2007)."The sonic hedgehog signaling network in development and neoplasia." Adv Anat Pathol 14(5):344-52.
Chen,B.Y.,D.P.Lin,et al.(2006)."A mouse prostate cancer model induced by Hedgehog overexpression." J Biomed Sci 13(3):373-84.
Chen,J.K.,J.Taipale,et al.(2002)."Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened." Genes Dev 16(21):2743-8.
Chen,J.K.,J.Taipale,et al.(2002)."Small molecule modulation of Smoothened activity." Proc Natl Acad Sci U S A 99(22):14071-6.
Chen,X.,A.Hoffuchi,et al.(2007)."Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation:it's inhibition leads to growth suppression and apoptosis."Cancer Sci 98(1):68-76.
Chen,X.L.,L.Q.Cao,et al.(2008)."Gli-1 siRNA induced apoptosis in Huh7 cells." World J Gastroenterol 14(4):582-9.
Chi,S.,S.Huang,et al.(2006)."Activation of the hedgehog pathway in a subset of lung cancers."Cancer Lett 244(1):53-60.
Clement,V.,P.Sanchez,et al.(2007)."HEDGEHOG-GLI1 signaling regulates human glioma growth,cancer stem cell self-renewal,and tumorigenicity." Curr Biol 17(2):165-72.
Clements,W.M.,J.Wang,et al.(2002)."beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer." Cancer Res 62(12):3503-6.
Cohen,M.M.,Jr.(2003)."The hedgehog signaling network." Am J Med Genet A 123A(1):5-28.
Corbit,K.C.,P.Aanstad,et al.(2005)."Vertebrate Smoothened functions at the primary cilium."Nature 437(7061):1018-21.
Day,T.F.and Y.Yang(2008)."Wnt and hedgehog signaling pathways in bone development." J Bone Joint Surg Am 90 Suppl 1:19-24.
Elia,D.,D.Madhala,et al.(2007)."Sonic hedgehog promotes proliferation and differentiation of adult muscle cells:Involvement of MAPK/ERK and PI3K/Akt pathways." Biochim Biophys Acta 1773(9):1438-46.
Escano,M.F.,S.Fujii,et al.(2000)."Expression of Sonic hedgehog and retinal opsin genes in experimentally-induced myopic chick eyes." Exp Eye Res 71(5):459-67.
Fan,L.,C.V.Pepicelli,et al.(2004)."Hedgehog signaling promotes prostate xenograft tumor growth." Endocrinology 145(8):3961-70.
Farazi,P.A.,J.Glickman,et al.(2006)."Cooperative interactions of p53 mutation,telomere dysfunction,and chronic liver damage in hepatocellular carcinoma progression." Cancer Res 66(9):4766-73.
Fong,C.W.,M.S.Chua,et al.(2006)."Sprouty 2,an inhibitor of mitogen-activated protein kinase signaling,is down-regulated in hepatocellular carcinoma." Cancer Res 66(4):2048-58.
Frank-Kamenetsky,M.,X.M.Zhang,et al.(2002)."Small-molecule modulators of Hedgehog signaling:identification and characterization of Smoothened agonists and antagonists." J Biol 1(2):10.
Fu,X.,Q.Wang,et al.(2008)."Expression patterns and polymorphisms of PTCH in Chinese hepatocellular carcinoma patients." Exp Mol Pathol 84(3):195-9.
Gulacsi,A.and L.Lillien(2003)."Sonic hedgehog and bone morphogenetic protein regulate interneuron development from dorsal telencephalic progenitors in vitro." J Neurosci 23(30):9862-72.
Hallahan,A.R.,J.I.Pritchard,et al.(2004)."The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas." Cancer Res 64(21):7794-800.
Hammerschmidt,M.,A.Brook,et al.(1997)."The world according to hedgehog." Trends Genet 13(1):14-21.
Hatsell,S.and A.R.Frost(2007)."Hedgehog signaling in mammary gland development and breast cancer." J Mammary Gland Biol Neoplasia 12(2-3):163-73.
Haycraft,C.J.,B.Banizs,et al.(2005)."Gli2 and Gli3 localize to cilia and require the intraflagellar Iransport protein polaris for processing and function." PLoS Genet 1(4):e53.
He,J.,T.Sheng,et al.(2006)."Suppressing Wnt signaling by the hedgehog pathway through sFRP-1." J Biol Chem 281(47):35598-602.
Huang,S.,J.He,et al.(2006)."Activation of the hedgehog pathway in human hepatocellular carcinomas." Carcinogenesis 27(7):1334-40.
Huangfu,D.and K.V.Anderson(2006)."Signaling from Smo to Ci/Gli:conservation and divergence of Hedgehog pathways from Drosophila to vertebrates." Development 133(1):3-14.
Huber,M.A.,N.Kraut,et al.(2005)."Molecular requirements for epithelial-mesenchymal transition during tumor progression." Curr Opin Cell Biol 17(5):548-58.
Hulit,J.,R.J.Lee,et al.(2006)."p27Kipl repression of ErbB2-induced mammary tumor growth in transgenic mice involves Skp2 and Wnt/beta-catenin signaling." Cancer Res 66(17):8529-41.
Hwang,I.T.,Y.M.Chung,et al.(2007)."Drug resistance to 5-FU linked to reactive oxygen species modulator 1." Biochem Biophys Res Commun 359(2):304-10.
Hynes,M.,J.A.Porter,et al.(1995)."Induction of midbrain dopaminergic neurons by Sonic hedgehog." Neuron 15(1):35-44.
Ijichi,K.,M.Adachi,et al.(2008)."Pretreatment with 5-FU enhances cisplatin cytotoxicity in head and neck squamous cell carcinoma cells." Cancer Chemother Pharmacol 62(5):745-52.
Incardona,J.P.,W.Gaffield,et al.(2000)."Cyclopamine inhibition of Sonic hedgehog signal transduction is not mediated through effects on cholesterol transport." Dev Biol 224(2):440-52.
Ishikawa,T.,M.Imai,et al.(2007)."Improved survival for hepatocellular carcinoma with portal vein tumor thrombosis treated by intra-arterial chemotherapy combining etoposide,carboplatin,epirubicin and pharmacokinetic modulating chemotherapy by 5-FU and enteric-coated tegafur/uracil:a pilot study." World J Gastroenterol 13(41):5465-70.
Kalderon,D.(2002)."Similarities between the Hedgehog and Wnt signaling pathways." Trends Cell Biol 12(11):523-31.
Karhadkar,S.S.,G.S.Bova,et al.(2004)."Hedgehog signalling in prostate regeneration,neoplasia and metastasis." Nature 431(7009):707-12.
Katano,M.,H.Yamamoto,et al.(1987)."[A case of gastric cancer with multiple liver metastases responding to combination therapy of recombinant interferon-gamma(KW-2202) and 5-FU]." Gan To Kagaku Ryoho 14(12):3351-4.
Katoh,Y.and M.Katoh(2006)."WNT antagonist,SFRP1,is Hedgehog signaling target." Int J Mol Med 17(1):171-5.
Keeler,R.F.(1970)."Teratogenic compounds of Veratrum californicum(Durand) X.Cyclopia in rabbits produced by cyclopamine." Teratology 3(2):175-80.
Keeler,R.F.and D.C.Baker(1989)."Oral,osmotic minipump,and intramuscular administration to sheep of the Veratrum alkaloid cyclopamine." Proc Soc Exp Biol Med 192(2):153-6.
Keeler,R.F.and W.Binns(1968)."Teratogenic compounds of Veratrum califomicum(Durand).V.Comparison of cyclopian effects of steroidal alkaloids from the plant and structurally related compounds from other sources." Teratology 1(1):5-10.
Keith,A.and M.W.Flack(2004)."The auriculo-ventricular bundle of the human heart.1906." Ann Noninvasive Electrocardiol 9(4):400-9.
Kessaris,N.,F.Jamen,et al.(2004)."Cooperation between sonic hedgehog and fibroblast growth factor/MAPK signalling pathways in neocortical precursors." Development 131(6):1289-98.
Kim,R.,M.Emi,et al.(2005)."Chemosensitization by STI571 targeting the platelet-derived growth factor/platelet-derived growth factor receptor-signaling pathway in the tumor progression and angiogenesis of gastric carcinoma." Cancer 103(9):1800-9.
Kim,T.E.,H.S.Lee,et al.(2003)."Sonic hedgehog and FGF8 collaborate to induce dopaminergic phenotypes in the Nurr1-overexpressing neural stem cell." Biochem Biophys Res Commun 305(4):1040-8.
Kinto,N.,M.Iwamoto,et al.(1997)."Fibroblasts expressing Sonic hedgehog induce osteoblast differentiation and ectopic bone formation." FEBS Lett 404(2-3):319-23.
Koike,K.,A.Takaki,et al.(2006)."Combination of 5-FU and IFNalpha enhances IFN signaling pathway and caspase-8 activity,resulting in marked apoptosis in hepatoma cell lines." Int J Oncol 29(5):1253-61.
Kondoh,H.,M.Uchikawa,et al.(2000)."Zebrafish mutations in Gli-mediated hedgehog signaling lead to lens transdifferentiation from the adenohypophysis anlage." Mech Dev 96(2):165-74.
Kusano,K.F.,R.Pola,et al.(2005)."Sonic hedgehog myocardial gene therapy:tissue repair through transient reconstitution of embryonic signaling." Nat Med 11(11):1197-204.
Lavine,K.J.,A.Kovacs,et al.(2008)."Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice." J Clin Invest 118(7):2404-14.
Lavine,K.J.and D.M.Ornitz(2007)."Rebuilding the coronary vasculature:hedgehog as a new candidate for pharmacologic revascularization." Trends Cardiovasc Med 17(3):77-83.
Lee,C.S.,L.Buttitta,et al.(2001)."Evidence that the WNT-inducible growth arrest-specific gene 1encodes an antagonist of sonic hedgehog signaling in the somite." Proc Natl Acad Sci U S A 98(20):11347-52.
Lee,J.,J.R.Willer,et al.(2008)."Zebrafish blowout provides genetic evidence for Patchedl-mediated negative regulation of Hedgehog signaling within the proximal optic vesicle of the vertebrate eye." Dev Biol 319(1):10-22.
Lee,S.W.,M.A.Moskowitz,et al.(2007)."Sonic hedgehog inversely regulates the expression of angiopoietin-1 and angiopoietin-2 in fibroblasts." Int J Mol Med 19(3):445-51.
Lemjabbar-Alaoui,H.,V.Dasari,et al.(2006)."Wnt and Hedgehog are critical mediators of cigarette smoke-induced lung cancer." PLoS ONE 1:e93.
Li,X.,W.Deng,et al.(2007)."Glil acts through Snail and E-cadherin to promote nuclear signaling by beta-catenin." Oncogene 26(31):4489-98.
Li,X.,W.Deng,et al.(2006)."Snail induction is an early response to Glil that determines the efficiency of epithelial transformation." Oncogene 25(4):609-21.
Litingtung,Y.,L.Lei,et al.(1998)."Sonic hedgehog is essential to foregut development." Nat Genet 20(1):58-61.
Liu,S.,G.Dontu,et al.(2005)."Mammary stem cells,self-renewal pathways,and carcinogenesis."Breast Cancer Res 7(3):86-95.
Liu,W.J.,X.J.Wang,et al.(2006)."A single amino acid substitution in the West Nile virus nonstructural protein NS2A disables its ability to inhibit alpha/beta interferon induction and attenuates virus virulence in mice." J Virol 80(5):2396-404.
Ma,G.,Y.Xiao,et al.(2008)."AAA!!!_+Recent progress in the study of Hedgehog signaling." J Genet Genomics 35(3):129-37.
Ma,X.,K.Chen,et al.(2005)."Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas." Carcinogenesis 26(10):1698-705.
Ma,X.,T.Sheng,et al.(2006)."Hedgehog signaling is activated in subsets of esophageal cancers."Int J Cancer 118(1):139-48.
Ma,X.L.,H.J.Sun,et al.(2006)."Study of Sonic hedgehog signaling pathway related molecules in gastric carcinoma." World J Gastroenterol 12(25):3965-9.
Mak,K.K.,Y.Bi,et al.(2008)."Hedgehog signaling in mature osteoblasts regulates bone formation and resorption by controlling PTHrP and RANKL expression." Dev Cell 14(5):674-88.
Martin,S.T.,N.Sato,et al.(2005)."Aberrant methylation of the Human Hedgehog interacting protein(HHIP) gene in pancreatic neoplasms." Cancer Biol Ther 4(7):728-33.
Masaaki Ii,Miki Horii,et al.(2007)."Genetic Modification with Sonic Hedgehog Mitigates Aging-induced EPC Dysfunction and Augments Therapeutic Angiogenesis of Endogenous EPCs following Acute Myocardial Infarction." Circulation 116(Ⅱ_224).
Matsumura,Y.,M.Yashiro,et al.(2005)."5-Fluorouracil up-regulates interferon pathway gene expression in esophageal cancer cells." Anticancer Res 25(5):3271-8.
May,S.R.,A.M.Ashique,et al.(2005)."Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli."Dev Biol 287(2):378-89.
Meert,A.P.,B.Martin,et al.(2002)."The role of EGF-R expression on patient survival in lung cancer:a systematic review with meta-analysis." Eur Respir J 20(4):975-81.
Meric-Bernstam,F.and M.C.Hung(2006)."Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy." Clin Cancer Res 12(21):6326-30.
Mill,P.,R.Mo,et al.(2003)."Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development." Genes Dev 17(2):282-94.
Mimeault,M.,E.Moore,et al.(2006)."Cytotoxic effects induced by a combination of cyclopamine and gefitinib,the selective hedgehog and epidermal growth factor receptor signaling inhibitors,in prostate cancer cells." Int J Cancer 118(4):1022-31.
Moertel,C.G.,R.J.Reitemeier,et al.(1972)."Effect of concomitant drug treatment on toxic and therapeutic activity of 5-fluorouracil(5-FU;NSC-19893)." Cancer Chemother Rep 56(2):245-7.
Moles,J.P.(1998)."[The gene of Gorlin's syndrome(basocellular nevomatosis) and the revival of the developmental genes in human carcinogenesis]." Bull Cancer 85(3):207-8.
Morton,J.P.,M.E.Mongeau,et al.(2007)."Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis." Proc Natl Acad Sci U S A 104(12):5103-8.
Moshiri,A.,C.R.McGuire,et al.(2005)."Sonic hedgehog regulates proliferation of the retinal ciliary marginal zone in posthatch chicks." Dev Dyn 233(1):66-75.
Mukherjee,S.,N.Frolova,et al.(2006)."Hedgehog signaling and response to cyclopamine differ in epithelial and stromal cells in benign breast and breast cancer." Cancer Biol Ther 5(6):674-83.
Mullor,J.L.,N.Dahmane,et al.(2001)."Wnt signals are targets and mediators of Gli function." Curr Biol 11(10):769-73.
Nagano,H.,M.Sakon,et al.(2007)."Hepatic resection followed by IFN-alpha and 5-FU for advanced hepatocellular carcinoma with tumor thrombus in the major portal branch."Hepatogastroenterology 54(73):172-9.
Nakashima,H.,M.Nakamura,et al.(2006)."Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer." Cancer Res 66(14):7041-9.
Nemoto,T.,J.Horton,et al.(1982)."Comparison of four-combination chemotherapy programs in metastatic breast cancer:comparison of multiple drug therapy with cytoxan,5-FU and prednisone versus cytoxan and adriamycin,versus cytoxan,5-FU and adriamycin,versus cytoxan,5-FU and prednisone alternating with cytoxan and adriamycin." Cancer 49(10):1988-93.
Niemann,C.,A.B.Unden,et al.(2003)."Indian hedgehog and beta-catenin signaling:role in the sebaceous lineage of normal and neoplastic mammalian epidermis." Proc Natl Acad Sci U S A 100 Suppl 1:11873-80.
Ohtsuka,N.,K.Urase,et al.(2001)."Induction of bud formation of embryonic mouse tracheal epithelium by fibroblast growth factor plus transferrin in mesenchyme-free culture." Dev Dyn 222(2):263-72.
Osterlund,T.and P.Kogerman(2006)."Hedgehog signalling:how to get from Smo to Ci and Gli."Trends Cell Biol 16(4):176-80.
Palma,V.and A.Ruiz i Altaba(2004)."Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex." Development 131(2):337-45.
Pasca di Magliano,M.and M.Hebrok(2003)."Hedgehog signalling in cancer formation and maintenance." Nat Rev Cancer 3(12):903-11.
Pasca di Magliano,M.,S.Sekine,et al.(2006)."Hedgehog/Ras interactions regulate early stages of pancreatic cancer." Genes Dev 20(22):3161-73.
Pasmantier,M.W.,M.Coleman,et al.(1985)."Six-drug chemotherapy(hexamethylmelamine,doxorubicin,cisplatin,cyclophosphamide,methotrexate,and 5-FU;CHAMP-5) for ovarian carcinoma:altemating sequences of combination regimens." Cancer Treat Rep 69(6):689-93.
Patil,M.A.,J.Zhang,et al.(2006)."Hedgehog signaling in human hepatocellular carcinoma." Cancer Biol Ther 5(1):111-7.
Pepicelli,C.V.,P.M.Lewis,et al.(1998)."Sonic hedgehog regulates branching morphogenesis in the mammalian lung." Curt Biol 8(19):1083-6.
Perron,M.,S.Boy,et al.(2003)."A novel function for Hedgehog signalling in retinal pigment epithelium differentiation." Development 130(8):1565-77.
Price,M.A.(2006)."CKI,there's more than one:casein kinase I family members in Wnt and Hedgehog signaling." Genes Dev 20(4):399-410.
Qin,L.X.and Z.Y.Tang(2002)."The prognostic molecular markers in hepatocellular carcinoma."World J Gastroenterol 8(3):385-92.
Reddy,S.,T.Andl,et al.(2001)."Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis." Mech Dev 107(1-2):69-82.
Regl,G,M.Kasper,et al.(2004)."Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2." Cancer Res 64(21):7724-31.
Rubin,L.L.and F.J.de Sauvage(2006)."Targeting the Hedgehog pathway in cancer." Nat Rev Drug Discov 5(12):1026-33.
Sakai,Y.,F.Kusano,et al.(1994)."[A case of advanced gastric cancer with multiple liver metastases showing marked response to new combination chemotherapy using 5-FU,THP and MMC (FTM)]." Gan To Kagaku Ryoho 21(8):1271-4.
Sanchez,P.,A.M.Hernandez,et al.(2004)."Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling." Proc Natl Acad Sci U S A 101(34):12561-6.
Sarkar,L.,M.Cobourne,et al.(2000)."Wnt/Shh interactions regulate ectodermal boundary formation during mammalian tooth development." Proc Natl Acad Sci U S A 97(9):4520-4.
Sato,Y.,T.Ichida,et al.(2002)."Preoperative administration of 5-FU and interferon beta may prevent recurrence of hepatitis B and C virus." Am J Gastroenterol 97(1):215-6.
Saxena,N.K.,D.Sharma,et al.(2007)."Concomitant activation of the JAK/STAT,PI3K/AKT,and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells." Cancer Res 67(6):2497-507.
Schmidt-Ullrich,R.,D.J.Tobin,et al.(2006)."NF-kappaB transmits Eda Al/EdaR signalling to activate Shh and cyclin D1 expression,and controls post-initiation hair placode down growth." Development 133(6):1045-57.
Sengnpta,A.,D.Banerjee,et al.(2007)."Deregulation and cross talk among Sonic hedgehog,Wnt,Hox and Notch signaling in chronic myeloid leukemia progression." Leukemia 21(5):949-55.
Seo,H.Y.,D.S.Kim,et al.(2008)."Treatment outcomes of oxaliplatin,5-FU,and leucovorin as salvage therapy for patients with advanced or metastatic gastric cancer:a retrospective analysis." Cancer Chemother Pharmacol.
Shachaf,C.M.,A.M.Kopelman,et al.(2004)."MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer." Nature 431(7012):1112-7.
Shackel,N.A.,P.H.McGuinness,et al.(2001)."Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis:cDNA array analysis of intrahepatic differential gene expression." Gut 49(4):565-76.
Shackel,N.A.,P.H.McGuinness,et al.(2002)."Insights into the pathobiology of hepatitis C virus-associated cirrhosis:analysis of intrahepatic differential gene expression." Am J Pathol 160(2):641-54.
Sheng,T.,C.Li,et al.(2004)."Activation of the hedgehog pathway in advanced prostate cancer."Mol Cancer 3:29.
Sicklick,J.K.,Y.X.Li,et al.(2006)."Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis." Carcinogenesis 27(4):748-57.
Sicklick,J.K.,Y.X.Li,et al.(2006)."Hedgehog signaling maintains resident hepatic progenitors throughout life." Am J Physiol Gastrointest Liver Physiol 290(5):G859-70.
Sire,F.R.,N.Matsumoto,et al.(1983)."Specific craniofacial defects induced by jervine in the cultured rat embryo." Teratog Carcinog Mutagen 3(2):111-21.
Sims-Mourtada,J.,J.G.Izzo,et al.(2006)."Hedgehog:an attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response." Clin Cancer Res 12(21):6565-72.
Sterling,J.A.,B.O.Oyajobi,et al.(2006)."The hedgehog signaling molecule Gli2 induces parathyroid hormone-related peptide expression and osteolysis in metastatic human breast cancer cells." Cancer Res 66(15):7548-53.
Sterpetti,P.,L.Marucci,et al.(2006)."Cell proliferation and drug resistance in hepatocellular carcinoma are modulated by Rho GTPase signals." Am J Physiol Gastrointest Liver Physiol 290(4):G624-32.
Sundqvist,K.,L.O.Hafstrom,et al.(1978)."Treatment of liver cancer with regional intraarterial 5-FU infusion." Am J Surg 136(3):328-31.
Taipale,J.,J.K.Chen,et al.(2000)."Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine." Nature 406(6799):1005-9.
Takahashi,Y.,M.Ueno,et al.(1987)."[Regional intra-arterial infusion in combination chemotherapy with IFN-beta,MMC and 5-FU(beta-MF chemotherapy) in liver tumors]." Gan To Kagaku Ryoho 14(8):2513-6.
Takehara,T.,X.Liu,et al.(2001)."Expression and role of Bcl-xL in human hepatocellular carcinomas." Hepatology 34(1):55-61.
Tang,Y.,K.Kitisin,et al.(2008)."Progenitor/stem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling." Proc Natl Acad Sci U S A 105(7):2445-50.
Thayer,S.E,M.P.di Magliano,et al.(2003)."Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis." Nature 425(6960):851-6.
Tsuchida,K.,Y.Sunada,et al.(2006)."Inhibitors of the TGF-beta superfamily and their clinical applications." Mini Rev Med Chem 6(11):1255-61.
Turner,Y.T.,H.J.Bang,et al.(2006)."Sonic hedgehog pathway inhibition alters epididymal function as assessed by the development of sperm motility." J Androl 27(2):225-32.
van den Brink,G.R.,S.A.Bleuming,et al.(2004)."Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation." Nat Genet 36(3):277-82.
Vitale,F.V.,P.Romeo,et al.(2007)."Hepatic intra-arterial interferon alpha 2b-based imrnunotherapy combined with 5-fluorouracil(5-FU)-based systemic chemotherapy for patients with hepatocellular carcinoma(HCC) not responsive and/or not eligible for conventional treatments:a pilot study." Anticancer Res 27(6B):4077-81.
Volberding,P.A.,M.A.Friedman,et al.(1982)."Therapy of liver tumors metastatic from colorectal cancer with whole-liver radiation combined with 5-FU,adriamycin,and methotrexate."Cancer Chemother Pharmacol 9(1):17-21.
Waite,K.A.and C.Eng(2003)."From developmental disorder to heritable cancer:it's all in the BMP/TGF-beta family." Nat Rev Genet 4(10):763-73.
Wang,J.M.,B.L.Xiao,et al.(2007)."Effect of targeted magnetic nanoparticles containing 5-FU on expression of bcl-2,bax and caspase 3 in nude mice with transplanted human liver cancer."World J Gastroenterol 13(23):3171-5.
Wang,L.H.,Y.L.Choi,et al.(2006)."Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions." Mod Pathol 19(5):675-83.
Wang,Q.,P.Craig,et al.(2007)."Aberrant Hedgehog Signaling Represents a Novel Therapeutic Target in B Cell Lymphomas." Blood(ASH Annual Meeting Abstracts) 110:3582.
Wang,Y.,M.C.Wu,et al.(2002)."Prognostic significance of c-myc and AIB1 amplification in hepatocellular carcinoma.A broad survey using high-throughput tissue microarray." Cancer 95(11):2346-52.
Warburton,D.,S.Bellusci,et al.(2003)."Growth factor signaling in lung morphogenetic centers:automaticity,stereotypy and symmetry." Respir Res 4:5.
Xu,L.,C.Han,et al.(2006)."Cross-talk between peroxisome proliferator-activated receptor delta and cytosolic phospholipase A(2)alpha/cyclooxygenase-2/prostaglandin E(2) signaling pathways in human hepatocellular carcinoma cells." Cancer Res 66(24):11859-68.
Yanai,K.,M.Nakamura,et al.(2008)."Crosstalk of hedgehog and Wnt pathways in gastric cancer."Cancer Lett 263(1):145-56.
Zhou,B.P.,J.Deng,et al.(2004)."Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition." Nat Cell Biol 6(10):931-40.
Zhou,B.P.and M.C.Hung(2005)."Wnt,hedgehog and snail:sister pathways that control by GSK-3beta and beta-Trcp in the regulation of metastasis." Cell Cycle 4(6):772-6.
Zhou,J.X.,L.W.Jia,et al.(2006)."Role of sonic hedgehog in maintaining a pool of proliferating stem cells in the human fetal epidermis." Hum Reprod 21(7):1698-704.
Akiyoshi,T.,M.Nakamura,et al.(2006)."Glil,downregulated in colorectal cancers,inhibits proliferation of colon cancer cells involving Wnt signalling activation." Gut 55(7):991-9.
Bai,C.B.and A.L.Joyner(2001)."Glil can rescue the in vivo function of Gli2." Development 128(24):5161-72.
Bai,C.B.,D.Stephen,et al.(2004)."All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3." Dev Cell 6(1):103-15.
Barnes,E.A.,M.Kong,et al.(2001)."Patchedl interacts with cyclin B1 to regulate cell cycle progression." EMBO J 20(9):2214-23.
Basler,K.and G.Struhl(1994)."Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein." Nature 368(6468):208-14.
Beachy,P.A.,S.S.Karhadkar,et al.(2004)."Mending and malignancy." Nature 431(7007):402.
Berman,D.M.,S.S.Karhadkar,et al.(2002)."Medulloblastoma growth inhibition by hedgehog pathway blockade." Science 297(5586):1559-61.
Berman,D.M.,S.S.Karhadkar,et al.(2003)."Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours." Nature 425(6960):846-51.
Bigelow,R.L.,N.S.Chari,et al.(2004)."Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1." J Biol Chem 279(2):1197-205.
Bijlsma,M.F.,K.S.Borensztajn,et al.(2007)."Sonic hedgehog induces transcription-independent cytoskeletal rearrangement and migration regulated by arachidonate metabolites." Cell Signal 19(12):2596-604.
Bijlsma,M.F.,C.A.Spek,et al.(2006)."Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion." PLoS Biol 4(8):e232.
Callahan,C.A.,T.Ofstad,et al.(2004)."MIM/BEG4,a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription." Genes Dev 18(22):2724-9.
Cao,C.,Y.Sun,et al.(2006)."EGFR-mediated expression of aquaporin-3 is involved in human skin fibroblast migration." Biochem J 400(2):225-34.
Carlberger,G.and I.Ljungdahl(1971)."[5-FU excretion in anticarcinogenic therapy in liver cancer]."Nord Med 86(46):1360.
Carpenter,D.,D.M.Stone,et al.(1998)."Characterization of two patched receptors for the vertebrate hedgehog protein family." Proc Natl Acad Sci U S A 95(23):13630-4.
Chang,J.,Y.Hsu,et al.(2005)."Increase of Bax/Bcl-XL ratio and arrest of cell cycle by luteolin in immortalized human hepatoma cell line." Life Sci 76(16):1883-93.
Chen,J.K.,J.Taipale,et al.(2002)."Small molecule modulation of Smoothened activity." Proc Natl Acad Sci U S A 99(22):14071-6.
Chen,X.L.,L.Q.Cao,et al.(2008)."Gli-1 siRNA induced apoptosis in Huh7 cells." World J Gastroenterol 14(4):582-9.
Dahmane,N.,J.Lee,et al.(1997)."Activation of the transcription factor Glil and the Sonic hedgehog signalling pathway in skin tumours." Nature 389(6653):876-81.
Dahmane,N.,R Sanchez,et al.(2001)."The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis." Development 128(24):5201-12.
Deutsch,G.,J.Jung,et al.(2001)."A bipotential precursor population for pancreas and liver within the embryonic endoderm." Development 128(6):871-81.
Duman-Scheel,M.,L.Weng,et al.(2002)."Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E." Nature 417(6886):299-304.
Hahn,H.,C.Wicking,et al.(1996)."Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome." Cell 85(6):841-51.
Huang,S.,J.He,et al.(2006)."Activation of the hedgehog pathway in human hepatocellular carcinomas." Carcinogenesis 27(7):1334-40.
Johnson,R.L.,A.L.Rothman,et al.(1996)."Human homolog of patched,a candidate gene for the basal cell nevus syndrome." Science 272(5268):1668-71.
Jung,Y.,K.D.Brown,et al.(2008)."Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans." Gastroenterology 134(5):1532-43.
Karhadkar,S.S.,G.S.Bova,et al.(2004)."Hedgehog signalling in prostate regeneration,neoplasia and metastasis." Nature 431(7009):707-12.
Kim,Y.,J.W.Yoon,et al.(2007)."Selective down-regulation of glioma-associated oncogene 2inhibits the proliferation of hepatocellular carcinoma cells." Cancer Res 67(8):3583-93.
Kogerman,P.,T.Grimm,et al.(1999)."Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1." Nat Cell Biol 1(5):312-9.
Lee,J.J.,D.P.von Kessler,et al.(1992)."Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog." Cell 71(1):33-50.
Lenferink,A.E.,J.Magoon,et al.(2004)."Investigation of three new mouse mammary tumor cell lines as models for transforming growth factor(TGF)-beta and Neu pathway signaling studies:identification of a novel model for TGF-beta-induced epithelial-to-mesenchymal transition." Breast Cancer Res 6(5):R514-30.
Li,C.,S.Chi,et al.(2004)."IFNalpha induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling." Oncogene 23(8):1608-17.
Liou,G.I.,S.Matragoon,et al.(2002)."MAP kinase and beta-catenin signaling in HGF induced RPE migration." Mol Vis 8:483-93.
Matsumura,Y.,M.Yashiro,et al.(2005)."5-Fluorouracil up-regulates interferon pathway gene expression in esophageal cancer cells." Anticancer Res 25(5):3271-8.
Mohler,J.(1988)."Requirements for hedgehod,a segmental polarity gene,in patterning larval and adult cuticle of Drosophila." Genetics 120(4):1061-72.
Mohler,J.and K.Vani(1992)."Molecular organization and embryonic expression of the hedgehog gene involved in cell-cell communication in segmental patterning of Drosophila."Development 115(4):957-71.
Motoyama,J.,L.Milenkovic,et al.(2003)."Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification." Dev Biol 259(1):150-61.
Nilsson,M.,A.B.Unden,et al.(2000)."Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1." Proc Natl Acad Sci U S A 97(7):3438-43.
Nusslein-Volhard,C.and E.Wieschaus(1980)."Mutations affecting segment number and polarity in Drosophila." Nature 287(5785):795-801.
Omenetti,A.and A.M.Diehl(2008)."The adventures of sonic hedgehog in development and repair.Ⅱ.Sonic hedgehog and liver development,inflammation,and cancer." Am J Physiol Gastrointest Liver Physiol 294(3):G595-8.
Pasca di Magliano,M.and M.Hebrok(2003)."Hedgehog signalling in cancer formation and maintenance." Nat Rev Cancer 3(12):903-11.
Patil,M.A.,J.Zhang,et al.(2006)."Hedgehog signaling in human hepatocellular carcinoma." Cancer Biol Ther 5(1):111-7.
Pearse,R.V.,2nd,L.S.Collier,et al.(1999)."Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators." Dev Biol 212(2):323-36.
Rao,G.,C.A.Pedone,et al.(2003)."c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice." Neoplasia 5(3):198-204.
Rohatgi,R.,L.Milenkovic,et al.(2007)."Patchedl regulates hedgehog signaling at the primary cilium." Science 317(5836):372-6.
Ruiz i Altaba,A.,P.Sanchez,et al.(2002)."Gli and hedgehog in cancer:tumours,embryos and stem cells." Nat Rev Cancer 2(5):361-72.
Ruiz i Altaba,A.,B.Stecca,et al.(2004)."Hedgehog--Gli signaling in brain tumors:stem cells and paradevelopmental programs in cancer." Cancer Lett 204(2):145-57.
Sanchez,P.,A.M.Hernandez,et al.(2004)."Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling." Proc Natl Acad Sci U S A 101(34):12561-6.
Schlag,P.,P.Hohenberger,et al.(1990)."Hepatic arterial infusion(HAl) chemotherapy for liver metastases of colorectal cancer using 5-FU." Eur J Surg Oncol 16(2):99-104.
Sicklick,J.K.,Y.X.Li,et al.(2006)."Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis." Carcinogenesis 27(4):748-57.
Sprong,H.,P.van der Sluijs,et al.(2001)."How proteins move lipids and lipids move proteins." Nat Rev Mol Cell Biol 2(7):504-13.
Stone,D.M.,M.Hynes,et al.(1996)."The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog." Nature 384(6605):129-34.
Tabata,T.,S.Eaton,et al.(1992)."The Drosophila hedgehog gene is expressed specifically in posterior compartment cells and is a target of engrailed regulation." Genes Dev 6(12B):2635-45.
Taipale,J.,M.K.Cooper,et al.(2002)."Patched acts catalytically to suppress the activity of Smoothened." Nature 418(6900):892-7.
Tashiro,S.,T.Michiue,et al.(1993)."Structure and expression of hedgehog,a Drosophila segment-polarity gene required for cell-cell communication." Gene 124(2):183-9.
Taylor,M.D.,L.Liu,et al.(2002)."Mutations in SUFU predispose to medulloblastoma." Nat Genet 31(3):306-10.
Thayer,S.P.,M.P.di Magliano,et al.(2003)."Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis." Nature 425(6960):851-6.
Volberding,P.A.,M.A.Friedman,et al.(1982)."Therapy of liver tumors metastatic from colorectal cancer with whole-liver radiation combined with 5-FU,adriamycin,and methotrexate."Cancer Chemother Pharmacol 9(1):17-21.
Wang,G.,B.Wang,et al.(1999)."Protein kinase A antagonizes Hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus." Genes Dev 13(21):2828-37.
Watkins,D.N.,D.M.Berman,et al.(2003)."Hedgehog signaling:progenitor phenotype in small-cell lung cancer." Cell Cycle 2(3):196-8.
Watkins,D.N.,D.M.Berman,et al.(2003)."Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer." Nature 422(6929):313-7.
Xie,J.,M.Murone,et al.(1998)."Activating Smoothened mutations in sporadic basal-cell carcinoma." Nature 391(6662):90-2.
Yoo,Y.A.,M.H.Kang,et al.(2008)."Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway."Carcinogenesis 29(3):480-90.
Zavros,Y.(2008)."The adventures of sonic hedgehog in development and repair.Ⅳ.Sonic hedgehog processing,secretion,and function in the stomach." Am J Physiol Gastrointest Liver Physiol 294(5):G1105-8.
Zhang,X.M.,M.Ramalho-Santos,et al.(2001)."Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node." Cell 105(6):781-92.
Ali-Osman,F.,J.M.Bnmner,et al.(1997)."Prognostic significance of glutathione S-transferase pi expression and subcellular localization in human gliomas." Clin Cancer Res 3(12 Pt 1):2253-61.
Anda,T.,H.K.Shabani,et al.(2003)."Relationship between expression of O6-methylguanine-DNA methyltransferase,glutathione-S-transferase pi in glioblastoma and the survival of the patients treated with nimustine hydrochloride:an immunohistochemical analysis." Neurol Res 25(3):241-8.
Asai,A.,Y.Miyagi,et al.(1994)."Negative effects of wild-type p53 and s-Myc on cellular growth and tumorigenicity of glioma cells.Implication of the tumor suppressor genes for gene therapy." J Neurooncol 19(3):259-68.
Ayre,S.G.,D.Perez Garcia y Bellon,et al.(1990)."Neoadjuvant low-dose chemotherapy with insulin in breast carcinomas." Eur J Cancer 26(11-12):1262-3.
Bader,P.,F.Schilling,et al.(1999)."Expression analysis of multidrug resistance associated genes in neuroblastomas." Oncol Rep 6(5):1143-6.
Bamstedt,U.(2000)."A new method to estimate respiration rate of biological material based on the reduction of tetrazolium violet." J Exp Mar Bio Ecol 251(2):239-263.
Baselga,J.,L.Norton,et al.(1998)."Recombinant humanized anti-HER2 antibody(Herceptin)enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts." Cancer Res 58(13):2825-31.
Basu,A.and S.Haldar(1998)."The relationship between BcI2,Bax and p53:consequences for cell cycle progression and cell death." Mol Hum Reprod 4(12):1099-109.B
elanich,M.,M.Pastor,et al.(1996)."Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine." Cancer Res 56(4):783-8.
Benhattar,J.,J.P.Cerottini,et al.(1996)."p53 mutations as a possible predictor of response to chemotherapy in metastatic colorectal carcinomas." Int J Cancer 69(3):190-2.
Bennett,W.P.,M.C.Hollstein,et al.(1992)."p53 mutation and protein accumulation during multistage human esophageal carcinogenesis." Cancer Res 52(21):6092-7.
Bossi,G.and A.Sacchi(2007)."Restoration of wild-type p53 function in human cancer:relevance for tumor therapy." Head Neck 29(3):272-84.
Bray,D.A.,V.T.DeVita,et al.(1971)."Effects of 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU;NSC-79037) and its degradation products on progression of L 1210 cells through the cell cycle." Cancer Chemother Rep 55(3):215-20.
Buttke,T.M.and P.A.Sandstrom(1994)."Oxidative stress as a mediator of apoptosis." Immunol Today 15(1):7-10.
Camus,P.,S.Kudoh,et al.(2004)."Interstitial lung disease associated with drug therapy." Br J Cancer 91 Suppl 2:S18-23.
Cao,Y.,Q.H.Xia,et al.(2008)."Pharmacological effects of serum containing chinese medicine Bushen Huayu Jiedu Compound Recipe in lung cancer drug-resistance cells." Chin J Integr Med 14(1):46-50.
Caricchio,R.,D.Kovalenko,et al.(1999)."Apoptosis provoked by the oxidative stress inducer menadione(Vitamin K(3)) is mediated by the Fas/Fas ligand system." Clin Immunol 93(1):65-74.
Catalano,A.,L.Graciotti,et al.(2004)."Preclinical evaluation of the nonsteroidal anti-inflammatory agent celecoxib on malignant mesotheIioma chemoprevention." Int J Cancer 109(3):322-8.
Chan,K.T.and M.L.Lung(2004)."Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line." Cancer Chemother Pharmacol 53(6):519-26.
Chen,J.H.,J.L.Cao,et al.(2008)."T-2 toxin-induced apoptosis involving Fas,p53,Bcl-xL,Bcl-2,Bax and caspase-3 signaling pathways in human chondrocytes." J Zhejiang Univ Sci B 9(6):455-63.
Chen,Z.P.,A.Malapetsa,et al.(1997)."Evidence for nucleotide excision repair as a modifying factor of O6-methylguanine-DNA methyltransferase-mediated innate chloroethylnitrosourea resistance in human tumor cell lines." Mol Pharmacol 52(5):815-20.
Cnubben,N.H.,H.M.Wortelboer,et al.(2005)."Metabolism of ATP-binding cassette drug transporter inhibitors:complicating factor for multidrug resistance." Expert Opin Drug Metab Toxicol 1(2):219-32.
Conklin,K.A.(2004)."Chemotherapy-associated oxidative stress:impact on chemotherapeutic effectiveness." Integr Cancer Ther 3(4):294-300.
Datta,K.,P.Shah,et al.(2004)."Sensitizing glioma cells to cisplatin by abrogating the p53 response with antisense oligonucleotides." Cancer Gene Ther 11(8):525-31.
Decleves,X.,A.Fajac,et al.(2002)."Molecular and functional MDR1-Pgp and MRPs expression in human glioblastoma multiforme cell lines." Int J Cancer 98(2):173-80.
Demeule,M.,D.Shedid,et al.(2001)."Expression of multidrug-resistance P-glycoprotein(MDR1) in human brain tumors." Int J Cancer 93(1):62-6.
Desjardins,A.,J.N.Rich,et al.(2005)."Chemotherapy and novel therapeutic approaches in malignant gIioma." Front Biosci 10:2645-68.
Dufour,C.,J.Grill,et al.(2006)."High-grade glioma in children under 5 years of age:a chemotherapy only approach with the BBSFOP protocol." Eur J Cancer 42(17):2939-45.
Efeyan,A.,M.Collado,et al.(2007)."Genetic dissection of the role of p21Cipl/Wafl in p53-mediated tumour suppression." Oncogene 26(11):1645-9.
Efeyan,A.and M.Serrano(2007)."p53:guardian of the genome and policeman of the oncogenes."Cell Cycle 6(9):1006-10.
Egle,A.,A.Villunger,et al.(1997)."Expression of Apo-1/Fas(CD95),Bcl-2,Bax and Bcl-x in myeloma cell lines:relationship between responsiveness to anti-Fas mab and p53 functional status." Br J Haematol 97(2):418-28.
England,K.,C.O.Driscoll,et al.(2006)."ROS and protein oxidation in early stages of cytotoxic drug induced apoptosis." Free Radic Res 40(11):1124-37.
Ezer,R.,M.Alonso,et al.(2002)."Identification of glutathione S-transferase(GST) polymorphisms in brain tumors and association with susceptibility to pediatric astrocytomas." J Neurooncol 59(2):123-34.
Fornace,A.J.,Jr.,M.A.Papathanasiou,et al.(1990)."Expression of the O6-methylguanine-DNA methyltransferase gene MGMT in MER+ and MER- human tumor cells." Cancer Res 50(24):7908-11.
Francis,M.A.,P.S.Bagga,et al.(1997)."Incomplete complementation of the DNA repair defect in cockayne syndrome cells by the denV gene from bacteriophage T4 suggests a deficiency in base excision repair." Mutat Res 385(1):59-74.
Frost,P.and V.T.DeVita(1966)."Pigmentation due to a new antitumor agent.Effects of topical application of BCNU[1,3-bis(2-chloroethyl)-1-nitrosourea]." Arch Dermatol 94(3):265-8.
Fujimoto,S.and M.Ogawa(1980)."Therapeutic synergism elicited by the combination of 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride:synergistic cytocidal activity against L1210 cells in vitro." Gann 71(5):659-66.
Fujiwara,T.,S.Nakasone,et al.(1983)."[Effect of ACNU,a water-soluble nitrosourea,on cell cycle of cultured glioma cells-flow cytometric analysis]." Gan To Kagaku Ryoho 10(9):2055-61.
Gailani,S.and J.Kutcher(1973)."Preliminary clinical trial of 1-(2-chlorethyl)-3-(4-methylcyclohexyl)- 1 nitrosourea(NSC-95411)(MeCCNU) in human neoplasms." J Med 4(4):209-18.
Garcion,E.,A.Lamprecht,et al.(2006)."A new generation of anticancer,drug-loaded,colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats." Mol Cancer Ther 5(7):1710-22.
Garkavtsev,I.,A.Kazarov,et al.(1996)."Suppression of the novel growth inhibitor p331NG1promotes neoplastic transformation." Nat Genet 14(4):415-20.
Gellhorn,A.(1958)."The status of alkylating agents in clinical cancer chemotherapy." Ann N Y Acad Sci 68(3):1254-7.
Genka,S.,N.Shitara,et al.(1987)."Cell cycle perturbation of cultured C6 glioma cells following short-term contact with a low dose of ACNU." Cytometry 8(4):386-91.
Goodman,H.M.and G.J.Macdonald(1969)."The effects of hypophysectomy and growth hormone on the metabolism of adipose tissue of diabetic rats." Horm Metab Res 1(6):290-5.
Graham,J.M.,Jr.,K.Anyane-Yeboa,et al.(2001)."Cerebro-oculo-facio-skeletai syndrome with a nucleotide excision-repair defect and a mutated XPD gene,with prenatal diagnosis in a triplet pregnancy." Am J Hum Genet 69(2):291-300.
Guo,H.,L.Lai,et al.(2002)."Human glioma cells and undifferentiated primary astrocytes that express aberrant EAAT2 mRNA inhibit normal EAAT2 protein expression and prevent cell death." Mol Cell Neurosci 21(4):546-60.
Hannun,Y.A.(1997)."Apoptosis and the dilemma of cancer chemotherapy." Blood 89(6):1845-53.
Hara,A.,N.Sakai,et al.(1993)."Immunoblot analysis of the placental form of glutathione S-transferase in protein extracted from paraffin-embedded human glioma tissue." J Cancer Res Clin Oncol 119(8):493-6.
Hasegawa,H.,T.Hayakawa,et al.(1977)."[Chemotherapy of experimental glioma with nitrosoureas--comparison of water soluble ACNU and lipid soluble me-CCNU(author's transl)]." No To Shinkei 29(8):891-8.
Haslam,G.,M.Richter,et al.(2005)."Estimating the number of viable animal cells in multiwell culture--a tetrazolium-based assay." Anal Biochem 336(2):187-95.
Hayashi,S.,T.Kobayashi,et al.(2003)."Simple and rapid cell growth assay using tetrazolium violet coloring method for screening of organic solvent tolerant bacteria." J Biosci Bioeng 96(4):360-3.
Hayes,J.D.and D.J.Pulford(1995)."The glutathione S-transferase supergene family:regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance."Crit Rev Biochem Mol Biol 30(6):445-600.
Helbing,C.C.,C.Veillette,et al.(1997)."A novel candidate tumor suppressor,1NG1,is involved in the regulation of apoptosis." Cancer Res 57(7):1255-8.
Hill,S.A.and E.A.Neuwelt(1982)."Intra-arterial chemotherapy following blood-brain barrier disruption in a patient with malignant glioma." J Neurosurg Nurs 14(2):94-7.
Huang,T.Y.,N.Arita,et al.(1999)."ACNU,MTX and 5-FU penetration of rat brain tissue and tumors," J Neurooncol 45(1):9-17.
Huang,X.Z.,J.Wang,et al.(2008)."Emodin enhances cytotoxicity of chemotherapeutic drugs in prostate cancer cells:the mechanisms involve ROS-mediated suppression of multidrug resistance and hypoxia inducible factor-1." Cancer Biol Ther 7(3):468-75.
Hurst,C.J.,J.C.Blannon,et al.(1994)."Differential Effect of Tetrazolium Dyes upon Bacteriophage Plaque Assay Titers." Appl Environ Microbiol 60(9):3462-3465.
Ito,S.,T.Ohga,et al.(2005)."p53 mutation profiling of multiple esophageal carcinoma using laser capture microdissection to demonstrate field carcinogenesis." Int J Cancer 113(1):22-8.
Izaki,S.,H.Goto,et al.(2007)."Long-term follow-up of busulfan,etoposide,and nimustine hydrochloride(ACNU) or melphalan as conditioning regimens for childhood acute leukemia and lymphoma." Int J Hematol 86(3):253-60.
Jaksic,W.,S.Trudel,et al.(2005)."Clinical outcomes in t(4;14) multiple myeloma:a chemotherapy-sensitive disease characterized by rapid relapse and alkylating agent resistance." J Clin Oncol 23(28):7069-73.
Jin,P.,Q.L.Zhang,et al.(2002)."[Establishment of drug-resistance cell line of human glioma mediated by MGMT]." Zhongguo Yi Xue Ke Xue Yuan Xue Bao 24(6):596-600.
Jin,Z.J.(1980)."[Addition in drug combination(author's transl)]." Zhongguo Yao Li Xue Bao 1(2):70-6.
Johannessen,Y.C.,R.Bjerkvig,et al.(2008)."DNA repair and cancer stem-like cells - Potential parmers in glioma drug resistance?" Cancer Treat Rev 34(6):558-67.
Kanamaru,R.,M.Asamura,et al.(1980)."Studies on the mechanism of action of ACNU,1-(4-amino-2-methylpyrimidine-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride:effects on cultured HeLa S3 cells." Tohoku J Exp Med 132(4):431-41.
Kanaya,T.,S.Kyo,et al.(2000)."Adenoviral expression of p53 represses telomerase activity through down-regulation of human telomerase reverse transcriptase transcription." Clin Cancer Res 6(4):1239-47.
Kikuchi,Y.,J.Hirata,et al.(1993)."Enhancement of antiproliferative effect of cis-diamminedichloroplatinurn(Ⅱ) by clomiphene and tamoxifen in human ovarian cancer ceils." Gynecol Oncol 49(3):365-72.
Kim,H.E.,J.H.Oh,et al.(1999)."AAA!!
Ginsenoside RH-2 induces apoptotic cell death in rat C6 glioma via a reactive oxygen- and caspase-dependent but Bcl-X(L)-independent pathway." Life Sci 65(3):PL33-40.
Kim,H.H.,S.Sik Bang,et al.(2005)."Involvement of PKC and ROS in the cytotoxic mechanism of anti-leukemic decursin and its derivatives and their structure-activity relationship in human K562 erythroleukemia and U937 myeloleukemia cells." Cancer Lett 223(2):191-201.
Kojima,T.,Y.Ito,et al.(1983)."[Effects of a combination chemotherapy "VEMA" consisting of vincristine,cyclophosphamide,methotrexate and ACNU in the treatment of small cell bronchogenic carcinoma]." Gan To Kagaku Ryoho 10(6):1491-6.
Kong,Q.(2003)."The centrosome-centered cell-brain in apoptosis." Med Hypotheses 61(1):126-32.
Kong Q,Zhang N,et al.(2004)."Tetrazolium violet sensitizes tumor cells to chemotherapeutic agents." Proceedings of the American Association for Cancer Research(A556).
Kong,Q.,J.Sun,et al.(2002)."Cell brain crystallization for cancer therapy." Med Hypotheses 59(4):367-72.
Koutsogiannaki,S.,N.Evangelinos,et al.(2006)."Cytotoxic mechanisms of Zn2+ and Cd2+ involve Na+/H+ exchanger(NHE) activation by ROS." Aquat Toxicol 78(4):315-24.
Krishna,R.,G.de Jong,et al.(1997)."Pulsed exposure of SDZ PSC 833 to multidrug resistant P388/ADR and MCF7/ADR cells in the absence of anticancer drugs can fully restore sensitivity to doxorubicin." Anticancer Res 17(5A):3329-34.
Lenczewski,M.E.,S.T.McGavin,et al.(1996)."Comparison of automated and traditional minimum inhibitory concentration procedures for microbiological cosmetic preservatives." J AOAC Int 79(6):1294-9.
Li,D.,S.L.Yang,et al.(1995)."[Exploration of clinical study of antileukemia cell drug-resistance by traditional Chinese medicine]." Zhongguo Zhong Xi Yi Jie He Za Zhi 15(10):636-7.
Li,W.W.,J.Fan,et al.(1997)."Overexpression of p21waf1 leads to increased inhibition of E2F-1phosphorylation and sensitivity to anticancer drugs in retinoblastoma-negative human sarcoma cells." Cancer Res 57(11):2193-9.
Liang,X.,Y.Yang,et al.(2003)."[The variation of Caspase3 activity in tanshinone induced NB4cells apoptosis]." Sichuan Da Xue Xue Bao Yi Xue Ban 34(3):549-51.
Liebetrau,G.and W.Pielesch(1991)."[Interstitial lung diseases caused by long-term neurological-psychiatric drug therapy?]." Pneumologie 45(3):90-4.
Lisker,S.A.(1970)."Chemotherapy for malignant disease:the alkylating agents." Del Med J 42(5):127-30.
Liu,Y.W.,T.Sakaeda,et al.(2003)."Effects of reactive oxygen species on cell proliferation and death in HeLa cells and its MDR1-overexpressing derivative cell line." Biol Pharm Bull 26(2):278-81.
Lo,H.W.,G.R.Antoun,et al.(2004)."The human glutathione S-transferase P1 protein is phosphorylated and its metabolic function enhanced by the Ser/Thr protein kinases,cAMP-dependent protein kinase and protein kinase C,in glioblastoma cells." Cancer Res 64(24):9131-8.
Loewe,S.(1953)."The problem of synergism and antagonism of combined drugs."Arzneimittelforschung 3(6):285-90.
Matsumoto,Y.,N.Sasaoka,et al.(1992)."[Quantitative analysis of glutathione and glutathione S-transferase in human brain tumors,C6 rat glioma cells and drug resistant C6 cells]." N."No Shinkei Geka 20(10):1069-74.
Meguro,S.,T.Kobayashi,et al.(1982)."[The combination chemotherapy of vincristine,methotrexate,ACNU,and adriamycin for anaplastic carcinoma of the lung]." Gan To Kagaku Ryoho 9(6):1012-8.
Melkersson,K.I.,M.G.Scordo,et al.(2007)."Impact of CYP 1A2 and CYP2D6 polymorphisms on drug metabolism and on insulin and lipid elevations and insulin resistance in clozapine-treated patients." J Clin Psychiatry 68(5):697-704.
Miglietta,A.,M.L.Panno,et al.(2004)."Insulin can modulate MCF-7 cell response to paclitaxel."Cancer Lett 209(2):139-45.
Mori,T.,K.Mineura,et al.(1979)."[Chemotherapy of malignant brain tumor by a water-soluble anti-tumor nitrosourea,ACNU(author's transl)]." Neurol Med Chir(Tokyo) 19(12):1157-71.
Morrow,C.S.,P.K.Smitherman,et al.(1998)."Coordinated action of glutathione S-transferases (GSTs) and multidrug resistance protein 1(MRP1) in antineoplastic drug detoxification.Mechanism of GST Al-1- and MRP1-associated resistance to chlorambucil in MCF7 breast carcinoma cells." J Biol Chem 273(32):20114-20.
Nagane,M.(2008)."[Current topics of treatment for glioma and mechanism of drug resistance]." Gan To Kagaku Ryoho 35(6):918-25.
Nagane,M.,S.Shibui,et al.(1995)."Investigation of chemoresistance-related genes mRNA expression for selecting anticancer agents in successful adjuvant chemotherapy for a case of recurrent glioblastoma." Surg Neurol 44(5):462-8;discussion 468-70.
Nakagawa,H.,M.Hori,et al.(1979)."[The anti-tumor effect of ACNU and X-irradiation on mouse glioma(author's transl)]." No To Shinkei 31(9):927-36.
Nakagawa,T.,T.Kubota,et al.(2006)."Gene expression profiles of 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU)-resistant C6 rat glioma cells." J Neuroonco179(3):271-9.
Nakamura,M.,S.Tsunoda,et al.(1990)."[Immunohistochemical study of placental form of glutathione S-transferase in human brain tumors and fetal brains]." No To Shinkei 42(10):965-70.
Nakatsu,Y.,K.Hattori,et al.(1993)."Organization and expression of the human gene for O6-methylguanine-DNA methyltransferase." Mutat Res 293(2):119-32.
Nevins,J.R.(1990)."Adenovirus ElA-dependent trans-activation of transcription." Semin Cancer Biol 1(1):59-68.
Newcomb,E.W.(1995)."P53 gene mutations in lymphoid diseases and their possible relevance to drug resistance." Leuk Lymphoma 17(3-4):211-21.
NicAmhlaoibh,R.,M.Heenan,et al.(1999)."Altered expression of mRNAs for apoptosis-modulating proteins in a low level multidrug resistant variant of a human lung carcinoma cell line that also expresses mdr1 mRNA." Int J Cancer 82(3):368-76.
Ogawa,K.,Y.Yoshii,et al.(2006)."Hyperfractionated radiotherapy and multi-agent chemotherapy (procarbazine,ACNU and vincristine) for high-grade gliomas:a prospective study."Anticancer Res 26(3B):2457-62.
Ohyasiki,K.,A.Ohsumi,et al.(1982)."[Two cases of central nervous system leukemia which responded excellently to intra-arterial injection of ACNU]." Gan To Kagaku Ryoho 9(5):942-7.
Park,J.E.,J.H.Yang,et al.(2002)."Lipid peroxidation-mediated cytotoxicity and DNA damage in U937 cells." Biochimie 84(12):1199-205.
Pegg,A.E.(1990)."Mammalian O6-alkylguanine-DNA alkyltransferase:regulation and importance in response to alkylating carcinogenic and therapeutic agents." Cancer Res 50(19):6119-29.
Pegram,M.,S.Hsu,et al.(1999)."Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers." Oncogene 18(13):2241-51.
Perek,N.,F.Koumanov,et al.(2002)."Modulation of the multidrug resistance of glioma by glutathione levels depletion-interaction with Tc-99M-Sestamibi and Tc-99M-Tetrofosmin."Cancer Biother Radiopharm 17(3):291-302.
Pieper,R.O.,B.W.Futscher,et al.(1990)."Comparison of O-6-methylguanine DNA methyltransferase(MGMT) mRNA levels in Mer+ and Mer- human tumor cell lines containing the MGMT gene by the polymerase chain reaction technique." Cancer Commun 2(1):13-20.
Pietras,R.J.,B.M.Fendly,et al.(1994)."Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells." Oncogene 9(7):1829-38.
Qi,H.,H.Z.Chen,et al.(2002)."Caspase 3 gene expression and[Ca2+]i homeostasis underlying desipramine-induced C6 glioma cell apoptosis." Acta Pharmacol Sin 23(9):803-7.
Rainov,N.G.,K.Gorbatyuk,et al.(2008)."Clinical trials with intracerebral convection-enhanced delivery of targeted toxins in malignant glioma." Rev Recent C lin Trials 3(1):2-9.
Rajda,J.and P.D.Phatak(2005)."Reversible drug-induced interstitial pneumonitis following imatinib mesylate therapy." Am J Hematol 79(1):80-1.
Saijo,N.and H.Niitani(1980)."Experimental and clinical effect of ACNU in Japan with emphasis on small-cell carcinoma of the lung." Cancer Chemother Pharmacol 4(3):165-71.
Saile,B.,N.Matthes,et al.(2001)."The bcl,NFkappaB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells." Eur J Cell Biol 80(8):554-61.
Sasaki,Y.,N.Saijo,et al.(1985)."Phase Ⅱ of ACNU for non-small cell lung cancer." Eur J Cancer Clin Onco121(12):1557-9.
Schilter,B.,I.Perrin,et al.(1996)."Placental glutathione S-transferase(GST-P) induction as a potential mechanism for the anti-carcinogenic effect of the coffee-specific components cafestol and kahweol." Carcinogenesis 17(11):2377-84.
Shelling,A.N.(1997)."Role of p53 in drug resistance in ovarian cancer." Lancet 349(9054):744-5.
Sherr,C.J.(2004)."Principles of tumor suppression." Cell 116(2):235-46.
Smith,M.L.,I.T.Chen,et al.(1994)."Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen." Science 266(5189):1376-80.
Strauss,B.S.(1990)."The control of O6-methylguanine-DNA methyltransferase(MGMT) activity in mammalian cells:a pre-molecular view." Mutat Res 233(1-2):139-50.
Sturm,I.,A.G.Bosanquet,et al.(2003)."Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy." Cell Death Differ 10(4):477-84.
Sullivan,G.F.,J.M.Yang,et al.(2000)."Regulation of expression of the multidrug resistance protein MRP1 by p53 in human prostate cancer cells." J Clin Invest 105(9):1261-7.
Sun,J.J.,Z.Y.Wang,et al.(2006)."[Inhibiting cerebral glioma growth with continuous low-dose chemotherapy and cyclooxygenase-2 inhibitor in nude mice]." Beijing Da Xue Xue Bao 38(3):252-6.
Suzuki,Y.and R.Tanaka(1980)."[Anti-tumor effect of ACNU on experimental mouse brain tumors]." Neurol Med Chir(Tokyo) 20(4):405-13.
Swamy,M.V.,I.Cooma,et al.(2004)."Modulation of cyclooxygenase-2 activities by the combined action of celecoxib and decosahexaenoic acid:novel strategies for colon cancer prevention and treatment." Mol Cancer Ther 3(2):215-21.
Tamura,T.,M.Matsuzaki,et al.(1997)."Upregulation of interferon-alpha receptor expression in hydroxyurea-treated leukemia cell lines." J Investig Med 45(4):160-7.
Tanaka,M.,T.Nishigaki,et al.(1980)."Distribution,excretion,and metabolism of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea(ACNU) in rats and mice after iv administration." Cancer Treat Rep 64(4-5):575-80.
Tanaka,S.,H.Kamitani,et al.(2000)."Preliminary individual adjuvant therapy for gliomas based on the results of molecular biological analyses for drug-resistance genes." J Neurooncol 46(2):157-71.
Tanaka,S.,I.Kobayashi,et al.(2001)."Drug-resistance gene expression and progression of astrocytic tumors." Brain Tumor Pathol 18(2):131-7.
Tew,K.D.and Z.Ronai(1999)."GST function in drug and stress response." Drug Resist Updat 2(3):143-147.
Theis,J.G.,H.S.Chan,et al.(2000)."Assessment of systemic toxicity in children receiving chemotherapy with cyclosporine for sarcoma." Med Pediatr Oncol 34(4):242-9.
Thevenod,F.,J.M.Friedmann,et al.(2000)."Up-regulation of multidmg resistance P-glycoprotein via nuclear factor-kappaB activation protects kidney proximal tubule cells from cadmiumand reactive oxygen species-induced apoptosis." J Biol Chem 275(3):1887-96.
Tosi,P.,G.Visani,et al.(1994)."Hydroxyurea enhances 3'-azido-3'-deoxythymidine(AZT)cytotoxicity in human chronic myeloid leukemia models." Eur J Haematol 52(5):291-5.
Trejo-Solis,C.,G.Palencia,et al.(2005)."Cas IIgly induces apoptosis in glioma C6 cells in vitro and in vivo through caspase-dependent and caspase-independent mechanisms." Neoplasia 7(6):563-74.
Tsuruo,T.,H.Iida,et al.(1981)."Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil." Cancer Res 41(5):1967-72.
Uchino,S.,M.Noguchi,et al.(1993)."p53 mutation in gastric cancer:a genetic model for carcinogenesis is common to gastric and colorectal cancer." Int J Cancer 54(5):759-64.
Vahrmeijer,A.L.,J.H.van Dierendonck,et al.(1999)."Potentiation of the cytostatic effect of melphalan on colorectal cancer hepatic metastases by infusion of buthionine sulfoximine (BSO) in the rat:enhanced tumor glutathione depletion by infusion of BSO in the hepatic artery." Cancer Chemother Pharmacol 44(2):111-6.
von Bossanyi,P.,S.Diete,et al.(1997)."Immunohistochemical expression of P-glycoprotein and glutathione S-transferases in cerebral gliomas and response to chemotherapy." Acta Neuropathol 94(6):605-11.
Vordermark,D.,K.Ruprecht,et al.(2006)."Glioblastoma multiforme with oligodendroglial component(GBMO):favorable outcome after post-operative radiotherapy and chemotherapy with nimustine(ACNU) and teniposide(VM26)." BMC Cancer 6:247.
Warmann,S.,M.Hunger,et al.(2002)."The role of the MDR1 gene in the development of multidrug resistance in human hepatoblastoma:clinical course and in vivo model." Cancer 95(8):1795-801.
Wedge,S.R.,J.K.Porteous,et al.(1996)."3-aminobenzamide and/or O6-benzylguanine evaluated as an adjuvant to temozolomide or BCNU treatment in cell lines of variable mismatch repair status and O6-alkylguanine-DNA alkyltransferase activity." Br J Cancer 74(7):1030-6.
Weller,M.,B.Muller,et al.(2003)."Neuro-Oncology Working Group 01 trial of nimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved-field radiotherapy in the first-line treatment of malignant glioma." J Clin Onco121(17):3276-84.
Westphal,M.,D.C.Hilt,et al.(2003)."A phase 3 trial of local chemotherapy with biodegradable carmustine(BCNU) wafers(Gliadel wafers) in patients with primary malignant glioma." Neuro Oncol 5(2):79-88.
Wijnhoven,S.W.,H.J.Kool,et al.(2001)."DMBA-induced toxic and mutagenic responses vary dramatically between NER-deficient Xpa,Xpc and Csb mice." Carcinogenesis 22(7):1099-106.
Wiman,K.G.(2007)."Restoration of Wild-Type p53 Function in Human Tumors:Strategies for Efficient Cancer Therapy." Adv Cancer Res 97:321-38.
Winter,S.,H.Strik,et al.(2000)."Glutathione S-transferase and drag sensitivity in malignant glioma." J Neurol Sci 179(S 1-2):115-21.
Wolff,J.E.,S.Berrak,et al.(2008)."Nitrosourea efficacy in high-grade glioma:a survival gain analysis summarizing 504 cohorts with 24193 patients." J Neurooncol 88(1):57-63.
Wong,R.P.,W.P.Tsang,et al.(2007)."p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3." Mol Cancer Ther 6(3):1054-61.
Wu,Z.N.,C.L.Chan,et al.(1992)."Expression of human O6-methylguanine-DNA methyltransferase in a DNA excision repair-deficient Chinese hamster ovary cell line and its response to certain alkylating agents." Cancer Res 52(1):32-5.
Xia,R.,G.Lin,et al.(1998)."[A study of the GSH contents,GST activity and the expression of GST isoenzyme and MRP in drug-resistant leukemic cell lines]." Zhonghua Xue Ye Xue Za Zhi 19(5):247-9.
Yamada,K.,Y.Ushio,et al.(1981)."[Changes of blood-brain barrier in the ethylnitrosourea induced rat glioma(author's transl)]." No To Shinkei 33(12):1251-5.
Yang,L.Q.,D.C.Fang,et al.(2004)."Effect of NF-kappaB,survivin,Bci-2 and Caspase3 on apoptosis of gastric cancer cells induced by tumor necrosis factor related apoptosis inducing ligand." World J Gastroenterol 10(1):22-5.
Yoshida,J.,T.Wakabayashi,et al.(1985)."[Combination therapy with HU IFN-beta and ACNU against malignant brain tumors,Part 1.Experimental study in vitro]." Gan To Kagaku Ryoho 12(1):99-104.
Yoshida,T.,K.Shimizu,et al.(1987)."[Possibility of overcoming ACNU resistance in ACNU-resistant sublines of rat brain tumors in vitro by a calmodulin inhibitor]." No Shinkei Geka 15(2):143-9.
Yoshida,T.,K.Shimizu,et al.(1987)."Modulation in vitro and in vivo of ACNU resistance in a subline of C6 glioma with reserpine." J Neurosurg 66(2):251-5.
Yu,Z.,J.Chen,et al.(1999)."Human DNA repair systems:an overview." Environ Mol Mutagen 33(1):3-20.
Zassler,B.,I.E.Blasig,et al.(2005)."Protein delivery of caspase-3 induces cell death in malignant C6 glioma,primary astrocytes and immortalized and primary brain capillary endothelial cells." J Neurooncol 71(2):127-34.
Zhang,J.P.,H.L.Shi,et al.(2006)."[Individualized chemotherapy based on drug sensitivity and resistance assay and MGMT protein expression for patients with malignant glioma--analysis of 42 cases]." Ai Zheng 25(12):1533-7.
Zhang,L.,D.Yu,et al.(2000)."Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression." Cancer Res 60(13):3655-61.
Zhao,Y.,N.Zhang,et al.(2006)."Tetrazolium violet induces G0/G1 arrest and apoptosis in brain tumor cells." J Neurooncol 77(2):109-15.
Zhao,Y.F.and Q.Z.Kong(2008)."Tetrazolium violet inhibits cell growth and induces cell death in C127 mouse breast tumor cells." Chem Biol Interact 174(1):19-26.
Zikan,V.,M.Semonsky,et al.(1979)."[Chemotherapy of malignant tumor growth.III.Substances with an alkylating effect]." Cesk Farm 28(2):62-81.
Znaidi,S.,S.Weber,et al.(2008)."Genomewide location analysis of Candida albicans Upc2p,a regulator of sterol metabolism and azole drug resistance." Eukaryot Cell 7(5):836-47.
朱春雷,张.,王运杰(2004].“亚甲蓝对C6细胞的促凋亡作用及其与BCNU协同抗肿瘤作用的研究.”且空瘟24(1):4.
李娜(2007).”盐酸小檗碱及联合应用顺铂诱导宫颈癌细胞株凋亡的研究.”佳木斯大学 硕士学位论文:53.
金澎,张.(2003).”MGMT反义RNA对人脑胶质瘤耐药性逆转的研究.”中国神经外科杂志 19:93-98.
郭建友,霍海如,姜廷良(2005).”衡量联合用药作用研究方法评价.”重要药理与临床 21(3):5.
傅相平,李安民(2008).”经颈动脉灌注ACNU与VM-26联合治疗复发性脑胶质瘤的临床研究.”Chinese Journal of Clinic Neurosurgery 13(3):168-169.
张翠(2006).“TV/O~6-BG与BCNU联合应用对小鼠乳腺癌细胞的抑制作用.”曲阜师范大学 硕士学位论文:37.
陈波,金.卢.(2004).”PKC抑制剂对MGC803细胞中P-gp的表达及耐药性的影响.”癌症 23(4):5.
马胜林,耿.(2001).”ACNU与Vm-26合用治疗脑瘤的实验研究.”Chinese Journal of Cancer 20(8):4.
Adams,J.M.and S.Cory(2001)."Life-or-death decisions by the Bcl-2 protein family." Trends Biochem Sci 26(1):61-6.
Agouni,A.,H.A.Mostefai,et al.(2007)."Sonic hedgehog carried by microparticles corrects endothelial injury through nitric oxide release." FASEB J 21(11):2735-41.
Alberts,D.S.,D.Garcia-Kendall,et al.(1988)."Phase Ⅱ trial of mitomycin C plus 5-FU in the treatment of drug-refractory ovarian cancer." Semin Oncol 15(3 Suppl 4):22-6.
Arai,Y.,C.Kido,et al.(1987)."[Preliminary results of a phase Ⅱ study of 5-FU,adriamycin,and mitomycin C(FAM) in combined hepatic infusion in patients with non-resectable metastatic liver cancer]." Gan To Kagaku Ryoho 14(7):2327-33.
Arango,D.,G.A.Corner,et al.(2001)."c-myc/p53 interaction determines sensitivity of human colon carcinoma cells to 5-fluorouracil in vitro and in vivo." Cancer Res 61(12):4910-5.
Arteaga,C.L.(2006)."Inhibition of TGFbeta signaling in cancer therapy." Curt Opin Genet Dev 16(1):30-7.
Asai,J.,H.Takenaka,et al.(2006)."Topical sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling."Circulation 113(20):2413-24.
Athar,M.,C.Li,et al.(2004)."Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis." Cancer Res 64(20):7545-52.
Bai,C.B.,W.Auerbach,et al.(2002)."Gli2,but not Gli1,is required for initial Shh signaling and ectopic activation of the Shh pathway." Development 129(20):4753-61.
Bai,C.B.,D.Stephen,et al.(2004)."All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3." Dev Cell 6(1):103-15.
Baron,M.(2001)."Induction of embryonic hematopoietic and endothelial stem/progenitor cells by hedgehog-mediated signals." Differentiation 68(4-5):175-85.
Beachy,P.A.,S.S.Karhadkar,et al.(2004)."Tissue repair and stem cell renewal in carcinogenesis." Nature 432(7015):324-31.
Bellusci,S.,Y.Furuta,et al.(1997)."Involvement of Sonic hedgehog(Shh) in mouse embryonic lung growth and morphogenesis." Development 124(1):53 -63.
Berman,D.M.,S.S.Karhadkar,et al.(2002)."Medulloblastoma growth inhibition by hedgehog pathway blockade." Science 297(5586):1559-61.
Berman,D.M.,S.S.Karhadkar,et al.(2003)."Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours." Nature 425(6960):846-51.
Bezard,E.,J.Baufreton,et al.(2003)."Sonic hedgehog is a neuromodulator in the adult subthalamic nucleus." FASEB J 17(15):2337-8.
Bigelow,R.L.,N.S.Chari,et al.(2004)."Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1." J Biol Chem 279(2):1197-205.
Bijlsma,M.F.,C.A.Spek,et al.(2006)."Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion." PLoS Biol 4(8):e232.
Blotta,S.and J.Negri(2007)."Hedgehog Pathway as a Potential Therapeutic Target in Multiple Myeloma." Blood(ASH Annual Meeting Abstracts) 110:672.
Bruix,J.,L.Boix,et al.(2004)."Focus on hepatocellular carcinoma." Cancer Cell 5(3):215-9.
Bryden,M.M.,H.E.Evans,et al.(1971)."Cyclopia in sheep caused by plant teratogens." J Anat 110(Pt 3):507.
Budhu,A.and X.W.Wang(2006)."The role of cytokines in hepatocellular carcinoma." J Leukoc Biol 80(6):1197-213.
Calcutt,N.A.,K.L.Allendoerfer,et al.(2003)."Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy." J Clin Invest 111(4):507-14.
Calvisi,D.F.and S.S.Thorgeirsson(2005)."Molecular mechanisms of hepatocarcinogenesis in transgenic mouse models of liver cancer." Toxicol Pathol 33(1):181-4.
Cao,Y.,J.Zhao,et al.(2003)."Expression of zebrafish Lc3 synthase gene in embryonic lens requires hedgehog signaling." Dev Dyn 228(3):308-12.
Caricasole,A.,A.Bakker,et al.(2005)."Two sides of the same coin:Wnt signaling in neurodegeneration and neuro-oncology." Biosci Rep 25(5-6):309-27.
Carlberger,G.and I.Ljungdahl(1971)."[5-FU excretion in anticarcinogenic therapy in liver cancer]."Nord Med 86(46):1360.
Cebra-Thomas,J.A.,J.Bromer,et al.(2003)."T-box gene products are required for mesenchymal induction of epithelial branching in the embryonic mouse lung." Dev Dyn 226(1):82-90.
Chan,C.F.,T.O.Yau,et al.(2004)."Evaluation of nuclear factor-kappaB,urokinase-type plasminogen activator,and HBχ and their clinicopathological significance in hepatocellular carcinoma." Clin Cancer Res 10(12 Pt 1):4140-9.
Chari,N.S.and T.J.McDonnell(2007)."The sonic hedgehog signaling network in development and neoplasia." Adv Anat Pathol 14(5):344-52.
Chen,B.Y.,D.P.Lin,et al.(2006)."A mouse prostate cancer model induced by Hedgehog overexpression." J Biomed Sci 13(3):373-84.
Chen,J.K.,J.Taipale,et al.(2002)."Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened." Genes Dev 16(21):2743-8.
Chen,J.K.,J.Taipale,et al.(2002)."Small molecule modulation of Smoothened activity." Proc Natl Acad Sci U S A 99(22):14071-6.
Chen,X.,A.Hoffuchi,et al.(2007)."Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation:it's inhibition leads to growth suppression and apoptosis."Cancer Sci 98(1):68-76.
Chen,X.L.,L.Q.Cao,et al.(2008)."Gli-1 siRNA induced apoptosis in Huh7 cells." World J Gastroenterol 14(4):582-9.
Chi,S.,S.Huang,et al.(2006)."Activation of the hedgehog pathway in a subset of lung cancers."Cancer Lett 244(1):53-60.
Clement,V.,P.Sanchez,et al.(2007)."HEDGEHOG-GLI1 signaling regulates human glioma growth,cancer stem cell self-renewal,and tumorigenicity." Curr Biol 17(2):165-72.
Clements,W.M.,J.Wang,et al.(2002)."beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer." Cancer Res 62(12):3503-6.
Cohen,M.M.,Jr.(2003)."The hedgehog signaling network." Am J Med Genet A 123A(1):5-28.
Corbit,K.C.,P.Aanstad,et al.(2005)."Vertebrate Smoothened functions at the primary cilium."Nature 437(7061):1018-21.
Day,T.F.and Y.Yang(2008)."Wnt and hedgehog signaling pathways in bone development." J Bone Joint Surg Am 90 Suppl 1:19-24.
Elia,D.,D.Madhala,et al.(2007)."Sonic hedgehog promotes proliferation and differentiation of adult muscle cells:Involvement of MAPK/ERK and PI3K/Akt pathways." Biochim Biophys Acta 1773(9):1438-46.
Escano,M.F.,S.Fujii,et al.(2000)."Expression of Sonic hedgehog and retinal opsin genes in experimentally-induced myopic chick eyes." Exp Eye Res 71(5):459-67.
Fan,L.,C.V.Pepicelli,et al.(2004)."Hedgehog signaling promotes prostate xenograft tumor growth." Endocrinology 145(8):3961-70.
Farazi,P.A.,J.Glickman,et al.(2006)."Cooperative interactions of p53 mutation,telomere dysfunction,and chronic liver damage in hepatocellular carcinoma progression." Cancer Res 66(9):4766-73.
Fong,C.W.,M.S.Chua,et al.(2006)."Sprouty 2,an inhibitor of mitogen-activated protein kinase signaling,is down-regulated in hepatocellular carcinoma." Cancer Res 66(4):2048-58.
Frank-Kamenetsky,M.,X.M.Zhang,et al.(2002)."Small-molecule modulators of Hedgehog signaling:identification and characterization of Smoothened agonists and antagonists." J Biol 1(2):10.
Fu,X.,Q.Wang,et al.(2008)."Expression patterns and polymorphisms of PTCH in Chinese hepatocellular carcinoma patients." Exp Mol Pathol 84(3):195-9.
Gulacsi,A.and L.Lillien(2003)."Sonic hedgehog and bone morphogenetic protein regulate interneuron development from dorsal telencephalic progenitors in vitro." J Neurosci 23(30):9862-72.
Hallahan,A.R.,J.I.Pritchard,et al.(2004)."The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas." Cancer Res 64(21):7794-800.
Hammerschmidt,M.,A.Brook,et al.(1997)."The world according to hedgehog." Trends Genet 13(1):14-21.
Hatsell,S.and A.R.Frost(2007)."Hedgehog signaling in mammary gland development and breast cancer." J Mammary Gland Biol Neoplasia 12(2-3):163-73.
Haycraft,C.J.,B.Banizs,et al.(2005)."Gli2 and Gli3 localize to cilia and require the intraflagellar Iransport protein polaris for processing and function." PLoS Genet 1(4):e53.
He,J.,T.Sheng,et al.(2006)."Suppressing Wnt signaling by the hedgehog pathway through sFRP-1." J Biol Chem 281(47):35598-602.
Huang,S.,J.He,et al.(2006)."Activation of the hedgehog pathway in human hepatocellular carcinomas." Carcinogenesis 27(7):1334-40.
Huangfu,D.and K.V.Anderson(2006)."Signaling from Smo to Ci/Gli:conservation and divergence of Hedgehog pathways from Drosophila to vertebrates." Development 133(1):3-14.
Huber,M.A.,N.Kraut,et al.(2005)."Molecular requirements for epithelial-mesenchymal transition during tumor progression." Curr Opin Cell Biol 17(5):548-58.
Hulit,J.,R.J.Lee,et al.(2006)."p27Kipl repression of ErbB2-induced mammary tumor growth in transgenic mice involves Skp2 and Wnt/beta-catenin signaling." Cancer Res 66(17):8529-41.
Hwang,I.T.,Y.M.Chung,et al.(2007)."Drug resistance to 5-FU linked to reactive oxygen species modulator 1." Biochem Biophys Res Commun 359(2):304-10.
Hynes,M.,J.A.Porter,et al.(1995)."Induction of midbrain dopaminergic neurons by Sonic hedgehog." Neuron 15(1):35-44.
Ijichi,K.,M.Adachi,et al.(2008)."Pretreatment with 5-FU enhances cisplatin cytotoxicity in head and neck squamous cell carcinoma cells." Cancer Chemother Pharmacol 62(5):745-52.
Incardona,J.P.,W.Gaffield,et al.(2000)."Cyclopamine inhibition of Sonic hedgehog signal transduction is not mediated through effects on cholesterol transport." Dev Biol 224(2):440-52.
Ishikawa,T.,M.Imai,et al.(2007)."Improved survival for hepatocellular carcinoma with portal vein tumor thrombosis treated by intra-arterial chemotherapy combining etoposide,carboplatin,epirubicin and pharmacokinetic modulating chemotherapy by 5-FU and enteric-coated tegafur/uracil:a pilot study." World J Gastroenterol 13(41):5465-70.
Kalderon,D.(2002)."Similarities between the Hedgehog and Wnt signaling pathways." Trends Cell Biol 12(11):523-31.
Karhadkar,S.S.,G.S.Bova,et al.(2004)."Hedgehog signalling in prostate regeneration,neoplasia and metastasis." Nature 431(7009):707-12.
Katano,M.,H.Yamamoto,et al.(1987)."[A case of gastric cancer with multiple liver metastases responding to combination therapy of recombinant interferon-gamma(KW-2202) and 5-FU]." Gan To Kagaku Ryoho 14(12):3351-4.
Katoh,Y.and M.Katoh(2006)."WNT antagonist,SFRP1,is Hedgehog signaling target." Int J Mol Med 17(1):171-5.
Keeler,R.F.(1970)."Teratogenic compounds of Veratrum californicum(Durand) X.Cyclopia in rabbits produced by cyclopamine." Teratology 3(2):175-80.
Keeler,R.F.and D.C.Baker(1989)."Oral,osmotic minipump,and intramuscular administration to sheep of the Veratrum alkaloid cyclopamine." Proc Soc Exp Biol Med 192(2):153-6.
Keeler,R.F.and W.Binns(1968)."Teratogenic compounds of Veratrum califomicum(Durand).V.Comparison of cyclopian effects of steroidal alkaloids from the plant and structurally related compounds from other sources." Teratology 1(1):5-10.
Keith,A.and M.W.Flack(2004)."The auriculo-ventricular bundle of the human heart.1906." Ann Noninvasive Electrocardiol 9(4):400-9.
Kessaris,N.,F.Jamen,et al.(2004)."Cooperation between sonic hedgehog and fibroblast growth factor/MAPK signalling pathways in neocortical precursors." Development 131(6):1289-98.
Kim,R.,M.Emi,et al.(2005)."Chemosensitization by STI571 targeting the platelet-derived growth factor/platelet-derived growth factor receptor-signaling pathway in the tumor progression and angiogenesis of gastric carcinoma." Cancer 103(9):1800-9.
Kim,T.E.,H.S.Lee,et al.(2003)."Sonic hedgehog and FGF8 collaborate to induce dopaminergic phenotypes in the Nurr1-overexpressing neural stem cell." Biochem Biophys Res Commun 305(4):1040-8.
Kinto,N.,M.Iwamoto,et al.(1997)."Fibroblasts expressing Sonic hedgehog induce osteoblast differentiation and ectopic bone formation." FEBS Lett 404(2-3):319-23.
Koike,K.,A.Takaki,et al.(2006)."Combination of 5-FU and IFNalpha enhances IFN signaling pathway and caspase-8 activity,resulting in marked apoptosis in hepatoma cell lines." Int J Oncol 29(5):1253-61.
Kondoh,H.,M.Uchikawa,et al.(2000)."Zebrafish mutations in Gli-mediated hedgehog signaling lead to lens transdifferentiation from the adenohypophysis anlage." Mech Dev 96(2):165-74.
Kusano,K.F.,R.Pola,et al.(2005)."Sonic hedgehog myocardial gene therapy:tissue repair through transient reconstitution of embryonic signaling." Nat Med 11(11):1197-204.
Lavine,K.J.,A.Kovacs,et al.(2008)."Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice." J Clin Invest 118(7):2404-14.
Lavine,K.J.and D.M.Ornitz(2007)."Rebuilding the coronary vasculature:hedgehog as a new candidate for pharmacologic revascularization." Trends Cardiovasc Med 17(3):77-83.
Lee,C.S.,L.Buttitta,et al.(2001)."Evidence that the WNT-inducible growth arrest-specific gene 1encodes an antagonist of sonic hedgehog signaling in the somite." Proc Natl Acad Sci U S A 98(20):11347-52.
Lee,J.,J.R.Willer,et al.(2008)."Zebrafish blowout provides genetic evidence for Patchedl-mediated negative regulation of Hedgehog signaling within the proximal optic vesicle of the vertebrate eye." Dev Biol 319(1):10-22.
Lee,S.W.,M.A.Moskowitz,et al.(2007)."Sonic hedgehog inversely regulates the expression of angiopoietin-1 and angiopoietin-2 in fibroblasts." Int J Mol Med 19(3):445-51.
Lemjabbar-Alaoui,H.,V.Dasari,et al.(2006)."Wnt and Hedgehog are critical mediators of cigarette smoke-induced lung cancer." PLoS ONE 1:e93.
Li,X.,W.Deng,et al.(2007)."Glil acts through Snail and E-cadherin to promote nuclear signaling by beta-catenin." Oncogene 26(31):4489-98.
Li,X.,W.Deng,et al.(2006)."Snail induction is an early response to Glil that determines the efficiency of epithelial transformation." Oncogene 25(4):609-21.
Litingtung,Y.,L.Lei,et al.(1998)."Sonic hedgehog is essential to foregut development." Nat Genet 20(1):58-61.
Liu,S.,G.Dontu,et al.(2005)."Mammary stem cells,self-renewal pathways,and carcinogenesis."Breast Cancer Res 7(3):86-95.
Liu,W.J.,X.J.Wang,et al.(2006)."A single amino acid substitution in the West Nile virus nonstructural protein NS2A disables its ability to inhibit alpha/beta interferon induction and attenuates virus virulence in mice." J Virol 80(5):2396-404.
Ma,G.,Y.Xiao,et al.(2008)."AAA!!!_+Recent progress in the study of Hedgehog signaling." J Genet Genomics 35(3):129-37.
Ma,X.,K.Chen,et al.(2005)."Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas." Carcinogenesis 26(10):1698-705.
Ma,X.,T.Sheng,et al.(2006)."Hedgehog signaling is activated in subsets of esophageal cancers."Int J Cancer 118(1):139-48.
Ma,X.L.,H.J.Sun,et al.(2006)."Study of Sonic hedgehog signaling pathway related molecules in gastric carcinoma." World J Gastroenterol 12(25):3965-9.
Mak,K.K.,Y.Bi,et al.(2008)."Hedgehog signaling in mature osteoblasts regulates bone formation and resorption by controlling PTHrP and RANKL expression." Dev Cell 14(5):674-88.
Martin,S.T.,N.Sato,et al.(2005)."Aberrant methylation of the Human Hedgehog interacting protein(HHIP) gene in pancreatic neoplasms." Cancer Biol Ther 4(7):728-33.
Masaaki Ii,Miki Horii,et al.(2007)."Genetic Modification with Sonic Hedgehog Mitigates Aging-induced EPC Dysfunction and Augments Therapeutic Angiogenesis of Endogenous EPCs following Acute Myocardial Infarction." Circulation 116(Ⅱ_224).
Matsumura,Y.,M.Yashiro,et al.(2005)."5-Fluorouracil up-regulates interferon pathway gene expression in esophageal cancer cells." Anticancer Res 25(5):3271-8.
May,S.R.,A.M.Ashique,et al.(2005)."Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli."Dev Biol 287(2):378-89.
Meert,A.P.,B.Martin,et al.(2002)."The role of EGF-R expression on patient survival in lung cancer:a systematic review with meta-analysis." Eur Respir J 20(4):975-81.
Meric-Bernstam,F.and M.C.Hung(2006)."Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy." Clin Cancer Res 12(21):6326-30.
Mill,P.,R.Mo,et al.(2003)."Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development." Genes Dev 17(2):282-94.
Mimeault,M.,E.Moore,et al.(2006)."Cytotoxic effects induced by a combination of cyclopamine and gefitinib,the selective hedgehog and epidermal growth factor receptor signaling inhibitors,in prostate cancer cells." Int J Cancer 118(4):1022-31.
Moertel,C.G.,R.J.Reitemeier,et al.(1972)."Effect of concomitant drug treatment on toxic and therapeutic activity of 5-fluorouracil(5-FU;NSC-19893)." Cancer Chemother Rep 56(2):245-7.
Moles,J.P.(1998)."[The gene of Gorlin's syndrome(basocellular nevomatosis) and the revival of the developmental genes in human carcinogenesis]." Bull Cancer 85(3):207-8.
Morton,J.P.,M.E.Mongeau,et al.(2007)."Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis." Proc Natl Acad Sci U S A 104(12):5103-8.
Moshiri,A.,C.R.McGuire,et al.(2005)."Sonic hedgehog regulates proliferation of the retinal ciliary marginal zone in posthatch chicks." Dev Dyn 233(1):66-75.
Mukherjee,S.,N.Frolova,et al.(2006)."Hedgehog signaling and response to cyclopamine differ in epithelial and stromal cells in benign breast and breast cancer." Cancer Biol Ther 5(6):674-83.
Mullor,J.L.,N.Dahmane,et al.(2001)."Wnt signals are targets and mediators of Gli function." Curr Biol 11(10):769-73.
Nagano,H.,M.Sakon,et al.(2007)."Hepatic resection followed by IFN-alpha and 5-FU for advanced hepatocellular carcinoma with tumor thrombus in the major portal branch."Hepatogastroenterology 54(73):172-9.
Nakashima,H.,M.Nakamura,et al.(2006)."Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer." Cancer Res 66(14):7041-9.
Nemoto,T.,J.Horton,et al.(1982)."Comparison of four-combination chemotherapy programs in metastatic breast cancer:comparison of multiple drug therapy with cytoxan,5-FU and prednisone versus cytoxan and adriamycin,versus cytoxan,5-FU and adriamycin,versus cytoxan,5-FU and prednisone alternating with cytoxan and adriamycin." Cancer 49(10):1988-93.
Niemann,C.,A.B.Unden,et al.(2003)."Indian hedgehog and beta-catenin signaling:role in the sebaceous lineage of normal and neoplastic mammalian epidermis." Proc Natl Acad Sci U S A 100 Suppl 1:11873-80.
Ohtsuka,N.,K.Urase,et al.(2001)."Induction of bud formation of embryonic mouse tracheal epithelium by fibroblast growth factor plus transferrin in mesenchyme-free culture." Dev Dyn 222(2):263-72.
Osterlund,T.and P.Kogerman(2006)."Hedgehog signalling:how to get from Smo to Ci and Gli."Trends Cell Biol 16(4):176-80.
Palma,V.and A.Ruiz i Altaba(2004)."Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex." Development 131(2):337-45.
Pasca di Magliano,M.and M.Hebrok(2003)."Hedgehog signalling in cancer formation and maintenance." Nat Rev Cancer 3(12):903-11.
Pasca di Magliano,M.,S.Sekine,et al.(2006)."Hedgehog/Ras interactions regulate early stages of pancreatic cancer." Genes Dev 20(22):3161-73.
Pasmantier,M.W.,M.Coleman,et al.(1985)."Six-drug chemotherapy(hexamethylmelamine,doxorubicin,cisplatin,cyclophosphamide,methotrexate,and 5-FU;CHAMP-5) for ovarian carcinoma:altemating sequences of combination regimens." Cancer Treat Rep 69(6):689-93.
Patil,M.A.,J.Zhang,et al.(2006)."Hedgehog signaling in human hepatocellular carcinoma." Cancer Biol Ther 5(1):111-7.
Pepicelli,C.V.,P.M.Lewis,et al.(1998)."Sonic hedgehog regulates branching morphogenesis in the mammalian lung." Curt Biol 8(19):1083-6.
Perron,M.,S.Boy,et al.(2003)."A novel function for Hedgehog signalling in retinal pigment epithelium differentiation." Development 130(8):1565-77.
Price,M.A.(2006)."CKI,there's more than one:casein kinase I family members in Wnt and Hedgehog signaling." Genes Dev 20(4):399-410.
Qin,L.X.and Z.Y.Tang(2002)."The prognostic molecular markers in hepatocellular carcinoma."World J Gastroenterol 8(3):385-92.
Reddy,S.,T.Andl,et al.(2001)."Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis." Mech Dev 107(1-2):69-82.
Regl,G,M.Kasper,et al.(2004)."Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2." Cancer Res 64(21):7724-31.
Rubin,L.L.and F.J.de Sauvage(2006)."Targeting the Hedgehog pathway in cancer." Nat Rev Drug Discov 5(12):1026-33.
Sakai,Y.,F.Kusano,et al.(1994)."[A case of advanced gastric cancer with multiple liver metastases showing marked response to new combination chemotherapy using 5-FU,THP and MMC (FTM)]." Gan To Kagaku Ryoho 21(8):1271-4.
Sanchez,P.,A.M.Hernandez,et al.(2004)."Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling." Proc Natl Acad Sci U S A 101(34):12561-6.
Sarkar,L.,M.Cobourne,et al.(2000)."Wnt/Shh interactions regulate ectodermal boundary formation during mammalian tooth development." Proc Natl Acad Sci U S A 97(9):4520-4.
Sato,Y.,T.Ichida,et al.(2002)."Preoperative administration of 5-FU and interferon beta may prevent recurrence of hepatitis B and C virus." Am J Gastroenterol 97(1):215-6.
Saxena,N.K.,D.Sharma,et al.(2007)."Concomitant activation of the JAK/STAT,PI3K/AKT,and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells." Cancer Res 67(6):2497-507.
Schmidt-Ullrich,R.,D.J.Tobin,et al.(2006)."NF-kappaB transmits Eda Al/EdaR signalling to activate Shh and cyclin D1 expression,and controls post-initiation hair placode down growth." Development 133(6):1045-57.
Sengnpta,A.,D.Banerjee,et al.(2007)."Deregulation and cross talk among Sonic hedgehog,Wnt,Hox and Notch signaling in chronic myeloid leukemia progression." Leukemia 21(5):949-55.
Seo,H.Y.,D.S.Kim,et al.(2008)."Treatment outcomes of oxaliplatin,5-FU,and leucovorin as salvage therapy for patients with advanced or metastatic gastric cancer:a retrospective analysis." Cancer Chemother Pharmacol.
Shachaf,C.M.,A.M.Kopelman,et al.(2004)."MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer." Nature 431(7012):1112-7.
Shackel,N.A.,P.H.McGuinness,et al.(2001)."Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis:cDNA array analysis of intrahepatic differential gene expression." Gut 49(4):565-76.
Shackel,N.A.,P.H.McGuinness,et al.(2002)."Insights into the pathobiology of hepatitis C virus-associated cirrhosis:analysis of intrahepatic differential gene expression." Am J Pathol 160(2):641-54.
Sheng,T.,C.Li,et al.(2004)."Activation of the hedgehog pathway in advanced prostate cancer."Mol Cancer 3:29.
Sicklick,J.K.,Y.X.Li,et al.(2006)."Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis." Carcinogenesis 27(4):748-57.
Sicklick,J.K.,Y.X.Li,et al.(2006)."Hedgehog signaling maintains resident hepatic progenitors throughout life." Am J Physiol Gastrointest Liver Physiol 290(5):G859-70.
Sire,F.R.,N.Matsumoto,et al.(1983)."Specific craniofacial defects induced by jervine in the cultured rat embryo." Teratog Carcinog Mutagen 3(2):111-21.
Sims-Mourtada,J.,J.G.Izzo,et al.(2006)."Hedgehog:an attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response." Clin Cancer Res 12(21):6565-72.
Sterling,J.A.,B.O.Oyajobi,et al.(2006)."The hedgehog signaling molecule Gli2 induces parathyroid hormone-related peptide expression and osteolysis in metastatic human breast cancer cells." Cancer Res 66(15):7548-53.
Sterpetti,P.,L.Marucci,et al.(2006)."Cell proliferation and drug resistance in hepatocellular carcinoma are modulated by Rho GTPase signals." Am J Physiol Gastrointest Liver Physiol 290(4):G624-32.
Sundqvist,K.,L.O.Hafstrom,et al.(1978)."Treatment of liver cancer with regional intraarterial 5-FU infusion." Am J Surg 136(3):328-31.
Taipale,J.,J.K.Chen,et al.(2000)."Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine." Nature 406(6799):1005-9.
Takahashi,Y.,M.Ueno,et al.(1987)."[Regional intra-arterial infusion in combination chemotherapy with IFN-beta,MMC and 5-FU(beta-MF chemotherapy) in liver tumors]." Gan To Kagaku Ryoho 14(8):2513-6.
Takehara,T.,X.Liu,et al.(2001)."Expression and role of Bcl-xL in human hepatocellular carcinomas." Hepatology 34(1):55-61.
Tang,Y.,K.Kitisin,et al.(2008)."Progenitor/stem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling." Proc Natl Acad Sci U S A 105(7):2445-50.
Thayer,S.E,M.P.di Magliano,et al.(2003)."Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis." Nature 425(6960):851-6.
Tsuchida,K.,Y.Sunada,et al.(2006)."Inhibitors of the TGF-beta superfamily and their clinical applications." Mini Rev Med Chem 6(11):1255-61.
Turner,Y.T.,H.J.Bang,et al.(2006)."Sonic hedgehog pathway inhibition alters epididymal function as assessed by the development of sperm motility." J Androl 27(2):225-32.
van den Brink,G.R.,S.A.Bleuming,et al.(2004)."Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation." Nat Genet 36(3):277-82.
Vitale,F.V.,P.Romeo,et al.(2007)."Hepatic intra-arterial interferon alpha 2b-based imrnunotherapy combined with 5-fluorouracil(5-FU)-based systemic chemotherapy for patients with hepatocellular carcinoma(HCC) not responsive and/or not eligible for conventional treatments:a pilot study." Anticancer Res 27(6B):4077-81.
Volberding,P.A.,M.A.Friedman,et al.(1982)."Therapy of liver tumors metastatic from colorectal cancer with whole-liver radiation combined with 5-FU,adriamycin,and methotrexate."Cancer Chemother Pharmacol 9(1):17-21.
Waite,K.A.and C.Eng(2003)."From developmental disorder to heritable cancer:it's all in the BMP/TGF-beta family." Nat Rev Genet 4(10):763-73.
Wang,J.M.,B.L.Xiao,et al.(2007)."Effect of targeted magnetic nanoparticles containing 5-FU on expression of bcl-2,bax and caspase 3 in nude mice with transplanted human liver cancer."World J Gastroenterol 13(23):3171-5.
Wang,L.H.,Y.L.Choi,et al.(2006)."Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions." Mod Pathol 19(5):675-83.
Wang,Q.,P.Craig,et al.(2007)."Aberrant Hedgehog Signaling Represents a Novel Therapeutic Target in B Cell Lymphomas." Blood(ASH Annual Meeting Abstracts) 110:3582.
Wang,Y.,M.C.Wu,et al.(2002)."Prognostic significance of c-myc and AIB1 amplification in hepatocellular carcinoma.A broad survey using high-throughput tissue microarray." Cancer 95(11):2346-52.
Warburton,D.,S.Bellusci,et al.(2003)."Growth factor signaling in lung morphogenetic centers:automaticity,stereotypy and symmetry." Respir Res 4:5.
Xu,L.,C.Han,et al.(2006)."Cross-talk between peroxisome proliferator-activated receptor delta and cytosolic phospholipase A(2)alpha/cyclooxygenase-2/prostaglandin E(2) signaling pathways in human hepatocellular carcinoma cells." Cancer Res 66(24):11859-68.
Yanai,K.,M.Nakamura,et al.(2008)."Crosstalk of hedgehog and Wnt pathways in gastric cancer."Cancer Lett 263(1):145-56.
Zhou,B.P.,J.Deng,et al.(2004)."Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition." Nat Cell Biol 6(10):931-40.
Zhou,B.P.and M.C.Hung(2005)."Wnt,hedgehog and snail:sister pathways that control by GSK-3beta and beta-Trcp in the regulation of metastasis." Cell Cycle 4(6):772-6.
Zhou,J.X.,L.W.Jia,et al.(2006)."Role of sonic hedgehog in maintaining a pool of proliferating stem cells in the human fetal epidermis." Hum Reprod 21(7):1698-704.
Akiyoshi,T.,M.Nakamura,et al.(2006)."Glil,downregulated in colorectal cancers,inhibits proliferation of colon cancer cells involving Wnt signalling activation." Gut 55(7):991-9.
Bai,C.B.and A.L.Joyner(2001)."Glil can rescue the in vivo function of Gli2." Development 128(24):5161-72.
Bai,C.B.,D.Stephen,et al.(2004)."All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3." Dev Cell 6(1):103-15.
Barnes,E.A.,M.Kong,et al.(2001)."Patchedl interacts with cyclin B1 to regulate cell cycle progression." EMBO J 20(9):2214-23.
Basler,K.and G.Struhl(1994)."Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein." Nature 368(6468):208-14.
Beachy,P.A.,S.S.Karhadkar,et al.(2004)."Mending and malignancy." Nature 431(7007):402.
Berman,D.M.,S.S.Karhadkar,et al.(2002)."Medulloblastoma growth inhibition by hedgehog pathway blockade." Science 297(5586):1559-61.
Berman,D.M.,S.S.Karhadkar,et al.(2003)."Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours." Nature 425(6960):846-51.
Bigelow,R.L.,N.S.Chari,et al.(2004)."Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1." J Biol Chem 279(2):1197-205.
Bijlsma,M.F.,K.S.Borensztajn,et al.(2007)."Sonic hedgehog induces transcription-independent cytoskeletal rearrangement and migration regulated by arachidonate metabolites." Cell Signal 19(12):2596-604.
Bijlsma,M.F.,C.A.Spek,et al.(2006)."Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion." PLoS Biol 4(8):e232.
Callahan,C.A.,T.Ofstad,et al.(2004)."MIM/BEG4,a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription." Genes Dev 18(22):2724-9.
Cao,C.,Y.Sun,et al.(2006)."EGFR-mediated expression of aquaporin-3 is involved in human skin fibroblast migration." Biochem J 400(2):225-34.
Carlberger,G.and I.Ljungdahl(1971)."[5-FU excretion in anticarcinogenic therapy in liver cancer]."Nord Med 86(46):1360.
Carpenter,D.,D.M.Stone,et al.(1998)."Characterization of two patched receptors for the vertebrate hedgehog protein family." Proc Natl Acad Sci U S A 95(23):13630-4.
Chang,J.,Y.Hsu,et al.(2005)."Increase of Bax/Bcl-XL ratio and arrest of cell cycle by luteolin in immortalized human hepatoma cell line." Life Sci 76(16):1883-93.
Chen,J.K.,J.Taipale,et al.(2002)."Small molecule modulation of Smoothened activity." Proc Natl Acad Sci U S A 99(22):14071-6.
Chen,X.L.,L.Q.Cao,et al.(2008)."Gli-1 siRNA induced apoptosis in Huh7 cells." World J Gastroenterol 14(4):582-9.
Dahmane,N.,J.Lee,et al.(1997)."Activation of the transcription factor Glil and the Sonic hedgehog signalling pathway in skin tumours." Nature 389(6653):876-81.
Dahmane,N.,R Sanchez,et al.(2001)."The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis." Development 128(24):5201-12.
Deutsch,G.,J.Jung,et al.(2001)."A bipotential precursor population for pancreas and liver within the embryonic endoderm." Development 128(6):871-81.
Duman-Scheel,M.,L.Weng,et al.(2002)."Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E." Nature 417(6886):299-304.
Hahn,H.,C.Wicking,et al.(1996)."Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome." Cell 85(6):841-51.
Huang,S.,J.He,et al.(2006)."Activation of the hedgehog pathway in human hepatocellular carcinomas." Carcinogenesis 27(7):1334-40.
Johnson,R.L.,A.L.Rothman,et al.(1996)."Human homolog of patched,a candidate gene for the basal cell nevus syndrome." Science 272(5268):1668-71.
Jung,Y.,K.D.Brown,et al.(2008)."Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans." Gastroenterology 134(5):1532-43.
Karhadkar,S.S.,G.S.Bova,et al.(2004)."Hedgehog signalling in prostate regeneration,neoplasia and metastasis." Nature 431(7009):707-12.
Kim,Y.,J.W.Yoon,et al.(2007)."Selective down-regulation of glioma-associated oncogene 2inhibits the proliferation of hepatocellular carcinoma cells." Cancer Res 67(8):3583-93.
Kogerman,P.,T.Grimm,et al.(1999)."Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1." Nat Cell Biol 1(5):312-9.
Lee,J.J.,D.P.von Kessler,et al.(1992)."Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog." Cell 71(1):33-50.
Lenferink,A.E.,J.Magoon,et al.(2004)."Investigation of three new mouse mammary tumor cell lines as models for transforming growth factor(TGF)-beta and Neu pathway signaling studies:identification of a novel model for TGF-beta-induced epithelial-to-mesenchymal transition." Breast Cancer Res 6(5):R514-30.
Li,C.,S.Chi,et al.(2004)."IFNalpha induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling." Oncogene 23(8):1608-17.
Liou,G.I.,S.Matragoon,et al.(2002)."MAP kinase and beta-catenin signaling in HGF induced RPE migration." Mol Vis 8:483-93.
Matsumura,Y.,M.Yashiro,et al.(2005)."5-Fluorouracil up-regulates interferon pathway gene expression in esophageal cancer cells." Anticancer Res 25(5):3271-8.
Mohler,J.(1988)."Requirements for hedgehod,a segmental polarity gene,in patterning larval and adult cuticle of Drosophila." Genetics 120(4):1061-72.
Mohler,J.and K.Vani(1992)."Molecular organization and embryonic expression of the hedgehog gene involved in cell-cell communication in segmental patterning of Drosophila."Development 115(4):957-71.
Motoyama,J.,L.Milenkovic,et al.(2003)."Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification." Dev Biol 259(1):150-61.
Nilsson,M.,A.B.Unden,et al.(2000)."Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1." Proc Natl Acad Sci U S A 97(7):3438-43.
Nusslein-Volhard,C.and E.Wieschaus(1980)."Mutations affecting segment number and polarity in Drosophila." Nature 287(5785):795-801.
Omenetti,A.and A.M.Diehl(2008)."The adventures of sonic hedgehog in development and repair.Ⅱ.Sonic hedgehog and liver development,inflammation,and cancer." Am J Physiol Gastrointest Liver Physiol 294(3):G595-8.
Pasca di Magliano,M.and M.Hebrok(2003)."Hedgehog signalling in cancer formation and maintenance." Nat Rev Cancer 3(12):903-11.
Patil,M.A.,J.Zhang,et al.(2006)."Hedgehog signaling in human hepatocellular carcinoma." Cancer Biol Ther 5(1):111-7.
Pearse,R.V.,2nd,L.S.Collier,et al.(1999)."Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators." Dev Biol 212(2):323-36.
Rao,G.,C.A.Pedone,et al.(2003)."c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice." Neoplasia 5(3):198-204.
Rohatgi,R.,L.Milenkovic,et al.(2007)."Patchedl regulates hedgehog signaling at the primary cilium." Science 317(5836):372-6.
Ruiz i Altaba,A.,P.Sanchez,et al.(2002)."Gli and hedgehog in cancer:tumours,embryos and stem cells." Nat Rev Cancer 2(5):361-72.
Ruiz i Altaba,A.,B.Stecca,et al.(2004)."Hedgehog--Gli signaling in brain tumors:stem cells and paradevelopmental programs in cancer." Cancer Lett 204(2):145-57.
Sanchez,P.,A.M.Hernandez,et al.(2004)."Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling." Proc Natl Acad Sci U S A 101(34):12561-6.
Schlag,P.,P.Hohenberger,et al.(1990)."Hepatic arterial infusion(HAl) chemotherapy for liver metastases of colorectal cancer using 5-FU." Eur J Surg Oncol 16(2):99-104.
Sicklick,J.K.,Y.X.Li,et al.(2006)."Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis." Carcinogenesis 27(4):748-57.
Sprong,H.,P.van der Sluijs,et al.(2001)."How proteins move lipids and lipids move proteins." Nat Rev Mol Cell Biol 2(7):504-13.
Stone,D.M.,M.Hynes,et al.(1996)."The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog." Nature 384(6605):129-34.
Tabata,T.,S.Eaton,et al.(1992)."The Drosophila hedgehog gene is expressed specifically in posterior compartment cells and is a target of engrailed regulation." Genes Dev 6(12B):2635-45.
Taipale,J.,M.K.Cooper,et al.(2002)."Patched acts catalytically to suppress the activity of Smoothened." Nature 418(6900):892-7.
Tashiro,S.,T.Michiue,et al.(1993)."Structure and expression of hedgehog,a Drosophila segment-polarity gene required for cell-cell communication." Gene 124(2):183-9.
Taylor,M.D.,L.Liu,et al.(2002)."Mutations in SUFU predispose to medulloblastoma." Nat Genet 31(3):306-10.
Thayer,S.P.,M.P.di Magliano,et al.(2003)."Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis." Nature 425(6960):851-6.
Volberding,P.A.,M.A.Friedman,et al.(1982)."Therapy of liver tumors metastatic from colorectal cancer with whole-liver radiation combined with 5-FU,adriamycin,and methotrexate."Cancer Chemother Pharmacol 9(1):17-21.
Wang,G.,B.Wang,et al.(1999)."Protein kinase A antagonizes Hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus." Genes Dev 13(21):2828-37.
Watkins,D.N.,D.M.Berman,et al.(2003)."Hedgehog signaling:progenitor phenotype in small-cell lung cancer." Cell Cycle 2(3):196-8.
Watkins,D.N.,D.M.Berman,et al.(2003)."Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer." Nature 422(6929):313-7.
Xie,J.,M.Murone,et al.(1998)."Activating Smoothened mutations in sporadic basal-cell carcinoma." Nature 391(6662):90-2.
Yoo,Y.A.,M.H.Kang,et al.(2008)."Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway."Carcinogenesis 29(3):480-90.
Zavros,Y.(2008)."The adventures of sonic hedgehog in development and repair.Ⅳ.Sonic hedgehog processing,secretion,and function in the stomach." Am J Physiol Gastrointest Liver Physiol 294(5):G1105-8.
Zhang,X.M.,M.Ramalho-Santos,et al.(2001)."Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node." Cell 105(6):781-92.
Ali-Osman,F.,J.M.Bnmner,et al.(1997)."Prognostic significance of glutathione S-transferase pi expression and subcellular localization in human gliomas." Clin Cancer Res 3(12 Pt 1):2253-61.
Anda,T.,H.K.Shabani,et al.(2003)."Relationship between expression of O6-methylguanine-DNA methyltransferase,glutathione-S-transferase pi in glioblastoma and the survival of the patients treated with nimustine hydrochloride:an immunohistochemical analysis." Neurol Res 25(3):241-8.
Asai,A.,Y.Miyagi,et al.(1994)."Negative effects of wild-type p53 and s-Myc on cellular growth and tumorigenicity of glioma cells.Implication of the tumor suppressor genes for gene therapy." J Neurooncol 19(3):259-68.
Ayre,S.G.,D.Perez Garcia y Bellon,et al.(1990)."Neoadjuvant low-dose chemotherapy with insulin in breast carcinomas." Eur J Cancer 26(11-12):1262-3.
Bader,P.,F.Schilling,et al.(1999)."Expression analysis of multidrug resistance associated genes in neuroblastomas." Oncol Rep 6(5):1143-6.
Bamstedt,U.(2000)."A new method to estimate respiration rate of biological material based on the reduction of tetrazolium violet." J Exp Mar Bio Ecol 251(2):239-263.
Baselga,J.,L.Norton,et al.(1998)."Recombinant humanized anti-HER2 antibody(Herceptin)enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts." Cancer Res 58(13):2825-31.
Basu,A.and S.Haldar(1998)."The relationship between BcI2,Bax and p53:consequences for cell cycle progression and cell death." Mol Hum Reprod 4(12):1099-109.B
elanich,M.,M.Pastor,et al.(1996)."Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine." Cancer Res 56(4):783-8.
Benhattar,J.,J.P.Cerottini,et al.(1996)."p53 mutations as a possible predictor of response to chemotherapy in metastatic colorectal carcinomas." Int J Cancer 69(3):190-2.
Bennett,W.P.,M.C.Hollstein,et al.(1992)."p53 mutation and protein accumulation during multistage human esophageal carcinogenesis." Cancer Res 52(21):6092-7.
Bossi,G.and A.Sacchi(2007)."Restoration of wild-type p53 function in human cancer:relevance for tumor therapy." Head Neck 29(3):272-84.
Bray,D.A.,V.T.DeVita,et al.(1971)."Effects of 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU;NSC-79037) and its degradation products on progression of L 1210 cells through the cell cycle." Cancer Chemother Rep 55(3):215-20.
Buttke,T.M.and P.A.Sandstrom(1994)."Oxidative stress as a mediator of apoptosis." Immunol Today 15(1):7-10.
Camus,P.,S.Kudoh,et al.(2004)."Interstitial lung disease associated with drug therapy." Br J Cancer 91 Suppl 2:S18-23.
Cao,Y.,Q.H.Xia,et al.(2008)."Pharmacological effects of serum containing chinese medicine Bushen Huayu Jiedu Compound Recipe in lung cancer drug-resistance cells." Chin J Integr Med 14(1):46-50.
Caricchio,R.,D.Kovalenko,et al.(1999)."Apoptosis provoked by the oxidative stress inducer menadione(Vitamin K(3)) is mediated by the Fas/Fas ligand system." Clin Immunol 93(1):65-74.
Catalano,A.,L.Graciotti,et al.(2004)."Preclinical evaluation of the nonsteroidal anti-inflammatory agent celecoxib on malignant mesotheIioma chemoprevention." Int J Cancer 109(3):322-8.
Chan,K.T.and M.L.Lung(2004)."Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line." Cancer Chemother Pharmacol 53(6):519-26.
Chen,J.H.,J.L.Cao,et al.(2008)."T-2 toxin-induced apoptosis involving Fas,p53,Bcl-xL,Bcl-2,Bax and caspase-3 signaling pathways in human chondrocytes." J Zhejiang Univ Sci B 9(6):455-63.
Chen,Z.P.,A.Malapetsa,et al.(1997)."Evidence for nucleotide excision repair as a modifying factor of O6-methylguanine-DNA methyltransferase-mediated innate chloroethylnitrosourea resistance in human tumor cell lines." Mol Pharmacol 52(5):815-20.
Cnubben,N.H.,H.M.Wortelboer,et al.(2005)."Metabolism of ATP-binding cassette drug transporter inhibitors:complicating factor for multidrug resistance." Expert Opin Drug Metab Toxicol 1(2):219-32.
Conklin,K.A.(2004)."Chemotherapy-associated oxidative stress:impact on chemotherapeutic effectiveness." Integr Cancer Ther 3(4):294-300.
Datta,K.,P.Shah,et al.(2004)."Sensitizing glioma cells to cisplatin by abrogating the p53 response with antisense oligonucleotides." Cancer Gene Ther 11(8):525-31.
Decleves,X.,A.Fajac,et al.(2002)."Molecular and functional MDR1-Pgp and MRPs expression in human glioblastoma multiforme cell lines." Int J Cancer 98(2):173-80.
Demeule,M.,D.Shedid,et al.(2001)."Expression of multidrug-resistance P-glycoprotein(MDR1) in human brain tumors." Int J Cancer 93(1):62-6.
Desjardins,A.,J.N.Rich,et al.(2005)."Chemotherapy and novel therapeutic approaches in malignant gIioma." Front Biosci 10:2645-68.
Dufour,C.,J.Grill,et al.(2006)."High-grade glioma in children under 5 years of age:a chemotherapy only approach with the BBSFOP protocol." Eur J Cancer 42(17):2939-45.
Efeyan,A.,M.Collado,et al.(2007)."Genetic dissection of the role of p21Cipl/Wafl in p53-mediated tumour suppression." Oncogene 26(11):1645-9.
Efeyan,A.and M.Serrano(2007)."p53:guardian of the genome and policeman of the oncogenes."Cell Cycle 6(9):1006-10.
Egle,A.,A.Villunger,et al.(1997)."Expression of Apo-1/Fas(CD95),Bcl-2,Bax and Bcl-x in myeloma cell lines:relationship between responsiveness to anti-Fas mab and p53 functional status." Br J Haematol 97(2):418-28.
England,K.,C.O.Driscoll,et al.(2006)."ROS and protein oxidation in early stages of cytotoxic drug induced apoptosis." Free Radic Res 40(11):1124-37.
Ezer,R.,M.Alonso,et al.(2002)."Identification of glutathione S-transferase(GST) polymorphisms in brain tumors and association with susceptibility to pediatric astrocytomas." J Neurooncol 59(2):123-34.
Fornace,A.J.,Jr.,M.A.Papathanasiou,et al.(1990)."Expression of the O6-methylguanine-DNA methyltransferase gene MGMT in MER+ and MER- human tumor cells." Cancer Res 50(24):7908-11.
Francis,M.A.,P.S.Bagga,et al.(1997)."Incomplete complementation of the DNA repair defect in cockayne syndrome cells by the denV gene from bacteriophage T4 suggests a deficiency in base excision repair." Mutat Res 385(1):59-74.
Frost,P.and V.T.DeVita(1966)."Pigmentation due to a new antitumor agent.Effects of topical application of BCNU[1,3-bis(2-chloroethyl)-1-nitrosourea]." Arch Dermatol 94(3):265-8.
Fujimoto,S.and M.Ogawa(1980)."Therapeutic synergism elicited by the combination of 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride:synergistic cytocidal activity against L1210 cells in vitro." Gann 71(5):659-66.
Fujiwara,T.,S.Nakasone,et al.(1983)."[Effect of ACNU,a water-soluble nitrosourea,on cell cycle of cultured glioma cells-flow cytometric analysis]." Gan To Kagaku Ryoho 10(9):2055-61.
Gailani,S.and J.Kutcher(1973)."Preliminary clinical trial of 1-(2-chlorethyl)-3-(4-methylcyclohexyl)- 1 nitrosourea(NSC-95411)(MeCCNU) in human neoplasms." J Med 4(4):209-18.
Garcion,E.,A.Lamprecht,et al.(2006)."A new generation of anticancer,drug-loaded,colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats." Mol Cancer Ther 5(7):1710-22.
Garkavtsev,I.,A.Kazarov,et al.(1996)."Suppression of the novel growth inhibitor p331NG1promotes neoplastic transformation." Nat Genet 14(4):415-20.
Gellhorn,A.(1958)."The status of alkylating agents in clinical cancer chemotherapy." Ann N Y Acad Sci 68(3):1254-7.
Genka,S.,N.Shitara,et al.(1987)."Cell cycle perturbation of cultured C6 glioma cells following short-term contact with a low dose of ACNU." Cytometry 8(4):386-91.
Goodman,H.M.and G.J.Macdonald(1969)."The effects of hypophysectomy and growth hormone on the metabolism of adipose tissue of diabetic rats." Horm Metab Res 1(6):290-5.
Graham,J.M.,Jr.,K.Anyane-Yeboa,et al.(2001)."Cerebro-oculo-facio-skeletai syndrome with a nucleotide excision-repair defect and a mutated XPD gene,with prenatal diagnosis in a triplet pregnancy." Am J Hum Genet 69(2):291-300.
Guo,H.,L.Lai,et al.(2002)."Human glioma cells and undifferentiated primary astrocytes that express aberrant EAAT2 mRNA inhibit normal EAAT2 protein expression and prevent cell death." Mol Cell Neurosci 21(4):546-60.
Hannun,Y.A.(1997)."Apoptosis and the dilemma of cancer chemotherapy." Blood 89(6):1845-53.
Hara,A.,N.Sakai,et al.(1993)."Immunoblot analysis of the placental form of glutathione S-transferase in protein extracted from paraffin-embedded human glioma tissue." J Cancer Res Clin Oncol 119(8):493-6.
Hasegawa,H.,T.Hayakawa,et al.(1977)."[Chemotherapy of experimental glioma with nitrosoureas--comparison of water soluble ACNU and lipid soluble me-CCNU(author's transl)]." No To Shinkei 29(8):891-8.
Haslam,G.,M.Richter,et al.(2005)."Estimating the number of viable animal cells in multiwell culture--a tetrazolium-based assay." Anal Biochem 336(2):187-95.
Hayashi,S.,T.Kobayashi,et al.(2003)."Simple and rapid cell growth assay using tetrazolium violet coloring method for screening of organic solvent tolerant bacteria." J Biosci Bioeng 96(4):360-3.
Hayes,J.D.and D.J.Pulford(1995)."The glutathione S-transferase supergene family:regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance."Crit Rev Biochem Mol Biol 30(6):445-600.
Helbing,C.C.,C.Veillette,et al.(1997)."A novel candidate tumor suppressor,1NG1,is involved in the regulation of apoptosis." Cancer Res 57(7):1255-8.
Hill,S.A.and E.A.Neuwelt(1982)."Intra-arterial chemotherapy following blood-brain barrier disruption in a patient with malignant glioma." J Neurosurg Nurs 14(2):94-7.
Huang,T.Y.,N.Arita,et al.(1999)."ACNU,MTX and 5-FU penetration of rat brain tissue and tumors," J Neurooncol 45(1):9-17.
Huang,X.Z.,J.Wang,et al.(2008)."Emodin enhances cytotoxicity of chemotherapeutic drugs in prostate cancer cells:the mechanisms involve ROS-mediated suppression of multidrug resistance and hypoxia inducible factor-1." Cancer Biol Ther 7(3):468-75.
Hurst,C.J.,J.C.Blannon,et al.(1994)."Differential Effect of Tetrazolium Dyes upon Bacteriophage Plaque Assay Titers." Appl Environ Microbiol 60(9):3462-3465.
Ito,S.,T.Ohga,et al.(2005)."p53 mutation profiling of multiple esophageal carcinoma using laser capture microdissection to demonstrate field carcinogenesis." Int J Cancer 113(1):22-8.
Izaki,S.,H.Goto,et al.(2007)."Long-term follow-up of busulfan,etoposide,and nimustine hydrochloride(ACNU) or melphalan as conditioning regimens for childhood acute leukemia and lymphoma." Int J Hematol 86(3):253-60.
Jaksic,W.,S.Trudel,et al.(2005)."Clinical outcomes in t(4;14) multiple myeloma:a chemotherapy-sensitive disease characterized by rapid relapse and alkylating agent resistance." J Clin Oncol 23(28):7069-73.
Jin,P.,Q.L.Zhang,et al.(2002)."[Establishment of drug-resistance cell line of human glioma mediated by MGMT]." Zhongguo Yi Xue Ke Xue Yuan Xue Bao 24(6):596-600.
Jin,Z.J.(1980)."[Addition in drug combination(author's transl)]." Zhongguo Yao Li Xue Bao 1(2):70-6.
Johannessen,Y.C.,R.Bjerkvig,et al.(2008)."DNA repair and cancer stem-like cells - Potential parmers in glioma drug resistance?" Cancer Treat Rev 34(6):558-67.
Kanamaru,R.,M.Asamura,et al.(1980)."Studies on the mechanism of action of ACNU,1-(4-amino-2-methylpyrimidine-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride:effects on cultured HeLa S3 cells." Tohoku J Exp Med 132(4):431-41.
Kanaya,T.,S.Kyo,et al.(2000)."Adenoviral expression of p53 represses telomerase activity through down-regulation of human telomerase reverse transcriptase transcription." Clin Cancer Res 6(4):1239-47.
Kikuchi,Y.,J.Hirata,et al.(1993)."Enhancement of antiproliferative effect of cis-diamminedichloroplatinurn(Ⅱ) by clomiphene and tamoxifen in human ovarian cancer ceils." Gynecol Oncol 49(3):365-72.
Kim,H.E.,J.H.Oh,et al.(1999)."AAA!!
Ginsenoside RH-2 induces apoptotic cell death in rat C6 glioma via a reactive oxygen- and caspase-dependent but Bcl-X(L)-independent pathway." Life Sci 65(3):PL33-40.
Kim,H.H.,S.Sik Bang,et al.(2005)."Involvement of PKC and ROS in the cytotoxic mechanism of anti-leukemic decursin and its derivatives and their structure-activity relationship in human K562 erythroleukemia and U937 myeloleukemia cells." Cancer Lett 223(2):191-201.
Kojima,T.,Y.Ito,et al.(1983)."[Effects of a combination chemotherapy "VEMA" consisting of vincristine,cyclophosphamide,methotrexate and ACNU in the treatment of small cell bronchogenic carcinoma]." Gan To Kagaku Ryoho 10(6):1491-6.
Kong,Q.(2003)."The centrosome-centered cell-brain in apoptosis." Med Hypotheses 61(1):126-32.
Kong Q,Zhang N,et al.(2004)."Tetrazolium violet sensitizes tumor cells to chemotherapeutic agents." Proceedings of the American Association for Cancer Research(A556).
Kong,Q.,J.Sun,et al.(2002)."Cell brain crystallization for cancer therapy." Med Hypotheses 59(4):367-72.
Koutsogiannaki,S.,N.Evangelinos,et al.(2006)."Cytotoxic mechanisms of Zn2+ and Cd2+ involve Na+/H+ exchanger(NHE) activation by ROS." Aquat Toxicol 78(4):315-24.
Krishna,R.,G.de Jong,et al.(1997)."Pulsed exposure of SDZ PSC 833 to multidrug resistant P388/ADR and MCF7/ADR cells in the absence of anticancer drugs can fully restore sensitivity to doxorubicin." Anticancer Res 17(5A):3329-34.
Lenczewski,M.E.,S.T.McGavin,et al.(1996)."Comparison of automated and traditional minimum inhibitory concentration procedures for microbiological cosmetic preservatives." J AOAC Int 79(6):1294-9.
Li,D.,S.L.Yang,et al.(1995)."[Exploration of clinical study of antileukemia cell drug-resistance by traditional Chinese medicine]." Zhongguo Zhong Xi Yi Jie He Za Zhi 15(10):636-7.
Li,W.W.,J.Fan,et al.(1997)."Overexpression of p21waf1 leads to increased inhibition of E2F-1phosphorylation and sensitivity to anticancer drugs in retinoblastoma-negative human sarcoma cells." Cancer Res 57(11):2193-9.
Liang,X.,Y.Yang,et al.(2003)."[The variation of Caspase3 activity in tanshinone induced NB4cells apoptosis]." Sichuan Da Xue Xue Bao Yi Xue Ban 34(3):549-51.
Liebetrau,G.and W.Pielesch(1991)."[Interstitial lung diseases caused by long-term neurological-psychiatric drug therapy?]." Pneumologie 45(3):90-4.
Lisker,S.A.(1970)."Chemotherapy for malignant disease:the alkylating agents." Del Med J 42(5):127-30.
Liu,Y.W.,T.Sakaeda,et al.(2003)."Effects of reactive oxygen species on cell proliferation and death in HeLa cells and its MDR1-overexpressing derivative cell line." Biol Pharm Bull 26(2):278-81.
Lo,H.W.,G.R.Antoun,et al.(2004)."The human glutathione S-transferase P1 protein is phosphorylated and its metabolic function enhanced by the Ser/Thr protein kinases,cAMP-dependent protein kinase and protein kinase C,in glioblastoma cells." Cancer Res 64(24):9131-8.
Loewe,S.(1953)."The problem of synergism and antagonism of combined drugs."Arzneimittelforschung 3(6):285-90.
Matsumoto,Y.,N.Sasaoka,et al.(1992)."[Quantitative analysis of glutathione and glutathione S-transferase in human brain tumors,C6 rat glioma cells and drug resistant C6 cells]." N."No Shinkei Geka 20(10):1069-74.
Meguro,S.,T.Kobayashi,et al.(1982)."[The combination chemotherapy of vincristine,methotrexate,ACNU,and adriamycin for anaplastic carcinoma of the lung]." Gan To Kagaku Ryoho 9(6):1012-8.
Melkersson,K.I.,M.G.Scordo,et al.(2007)."Impact of CYP 1A2 and CYP2D6 polymorphisms on drug metabolism and on insulin and lipid elevations and insulin resistance in clozapine-treated patients." J Clin Psychiatry 68(5):697-704.
Miglietta,A.,M.L.Panno,et al.(2004)."Insulin can modulate MCF-7 cell response to paclitaxel."Cancer Lett 209(2):139-45.
Mori,T.,K.Mineura,et al.(1979)."[Chemotherapy of malignant brain tumor by a water-soluble anti-tumor nitrosourea,ACNU(author's transl)]." Neurol Med Chir(Tokyo) 19(12):1157-71.
Morrow,C.S.,P.K.Smitherman,et al.(1998)."Coordinated action of glutathione S-transferases (GSTs) and multidrug resistance protein 1(MRP1) in antineoplastic drug detoxification.Mechanism of GST Al-1- and MRP1-associated resistance to chlorambucil in MCF7 breast carcinoma cells." J Biol Chem 273(32):20114-20.
Nagane,M.(2008)."[Current topics of treatment for glioma and mechanism of drug resistance]." Gan To Kagaku Ryoho 35(6):918-25.
Nagane,M.,S.Shibui,et al.(1995)."Investigation of chemoresistance-related genes mRNA expression for selecting anticancer agents in successful adjuvant chemotherapy for a case of recurrent glioblastoma." Surg Neurol 44(5):462-8;discussion 468-70.
Nakagawa,H.,M.Hori,et al.(1979)."[The anti-tumor effect of ACNU and X-irradiation on mouse glioma(author's transl)]." No To Shinkei 31(9):927-36.
Nakagawa,T.,T.Kubota,et al.(2006)."Gene expression profiles of 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU)-resistant C6 rat glioma cells." J Neuroonco179(3):271-9.
Nakamura,M.,S.Tsunoda,et al.(1990)."[Immunohistochemical study of placental form of glutathione S-transferase in human brain tumors and fetal brains]." No To Shinkei 42(10):965-70.
Nakatsu,Y.,K.Hattori,et al.(1993)."Organization and expression of the human gene for O6-methylguanine-DNA methyltransferase." Mutat Res 293(2):119-32.
Nevins,J.R.(1990)."Adenovirus ElA-dependent trans-activation of transcription." Semin Cancer Biol 1(1):59-68.
Newcomb,E.W.(1995)."P53 gene mutations in lymphoid diseases and their possible relevance to drug resistance." Leuk Lymphoma 17(3-4):211-21.
NicAmhlaoibh,R.,M.Heenan,et al.(1999)."Altered expression of mRNAs for apoptosis-modulating proteins in a low level multidrug resistant variant of a human lung carcinoma cell line that also expresses mdr1 mRNA." Int J Cancer 82(3):368-76.
Ogawa,K.,Y.Yoshii,et al.(2006)."Hyperfractionated radiotherapy and multi-agent chemotherapy (procarbazine,ACNU and vincristine) for high-grade gliomas:a prospective study."Anticancer Res 26(3B):2457-62.
Ohyasiki,K.,A.Ohsumi,et al.(1982)."[Two cases of central nervous system leukemia which responded excellently to intra-arterial injection of ACNU]." Gan To Kagaku Ryoho 9(5):942-7.
Park,J.E.,J.H.Yang,et al.(2002)."Lipid peroxidation-mediated cytotoxicity and DNA damage in U937 cells." Biochimie 84(12):1199-205.
Pegg,A.E.(1990)."Mammalian O6-alkylguanine-DNA alkyltransferase:regulation and importance in response to alkylating carcinogenic and therapeutic agents." Cancer Res 50(19):6119-29.
Pegram,M.,S.Hsu,et al.(1999)."Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers." Oncogene 18(13):2241-51.
Perek,N.,F.Koumanov,et al.(2002)."Modulation of the multidrug resistance of glioma by glutathione levels depletion-interaction with Tc-99M-Sestamibi and Tc-99M-Tetrofosmin."Cancer Biother Radiopharm 17(3):291-302.
Pieper,R.O.,B.W.Futscher,et al.(1990)."Comparison of O-6-methylguanine DNA methyltransferase(MGMT) mRNA levels in Mer+ and Mer- human tumor cell lines containing the MGMT gene by the polymerase chain reaction technique." Cancer Commun 2(1):13-20.
Pietras,R.J.,B.M.Fendly,et al.(1994)."Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells." Oncogene 9(7):1829-38.
Qi,H.,H.Z.Chen,et al.(2002)."Caspase 3 gene expression and[Ca2+]i homeostasis underlying desipramine-induced C6 glioma cell apoptosis." Acta Pharmacol Sin 23(9):803-7.
Rainov,N.G.,K.Gorbatyuk,et al.(2008)."Clinical trials with intracerebral convection-enhanced delivery of targeted toxins in malignant glioma." Rev Recent C lin Trials 3(1):2-9.
Rajda,J.and P.D.Phatak(2005)."Reversible drug-induced interstitial pneumonitis following imatinib mesylate therapy." Am J Hematol 79(1):80-1.
Saijo,N.and H.Niitani(1980)."Experimental and clinical effect of ACNU in Japan with emphasis on small-cell carcinoma of the lung." Cancer Chemother Pharmacol 4(3):165-71.
Saile,B.,N.Matthes,et al.(2001)."The bcl,NFkappaB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells." Eur J Cell Biol 80(8):554-61.
Sasaki,Y.,N.Saijo,et al.(1985)."Phase Ⅱ of ACNU for non-small cell lung cancer." Eur J Cancer Clin Onco121(12):1557-9.
Schilter,B.,I.Perrin,et al.(1996)."Placental glutathione S-transferase(GST-P) induction as a potential mechanism for the anti-carcinogenic effect of the coffee-specific components cafestol and kahweol." Carcinogenesis 17(11):2377-84.
Shelling,A.N.(1997)."Role of p53 in drug resistance in ovarian cancer." Lancet 349(9054):744-5.
Sherr,C.J.(2004)."Principles of tumor suppression." Cell 116(2):235-46.
Smith,M.L.,I.T.Chen,et al.(1994)."Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen." Science 266(5189):1376-80.
Strauss,B.S.(1990)."The control of O6-methylguanine-DNA methyltransferase(MGMT) activity in mammalian cells:a pre-molecular view." Mutat Res 233(1-2):139-50.
Sturm,I.,A.G.Bosanquet,et al.(2003)."Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy." Cell Death Differ 10(4):477-84.
Sullivan,G.F.,J.M.Yang,et al.(2000)."Regulation of expression of the multidrug resistance protein MRP1 by p53 in human prostate cancer cells." J Clin Invest 105(9):1261-7.
Sun,J.J.,Z.Y.Wang,et al.(2006)."[Inhibiting cerebral glioma growth with continuous low-dose chemotherapy and cyclooxygenase-2 inhibitor in nude mice]." Beijing Da Xue Xue Bao 38(3):252-6.
Suzuki,Y.and R.Tanaka(1980)."[Anti-tumor effect of ACNU on experimental mouse brain tumors]." Neurol Med Chir(Tokyo) 20(4):405-13.
Swamy,M.V.,I.Cooma,et al.(2004)."Modulation of cyclooxygenase-2 activities by the combined action of celecoxib and decosahexaenoic acid:novel strategies for colon cancer prevention and treatment." Mol Cancer Ther 3(2):215-21.
Tamura,T.,M.Matsuzaki,et al.(1997)."Upregulation of interferon-alpha receptor expression in hydroxyurea-treated leukemia cell lines." J Investig Med 45(4):160-7.
Tanaka,M.,T.Nishigaki,et al.(1980)."Distribution,excretion,and metabolism of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea(ACNU) in rats and mice after iv administration." Cancer Treat Rep 64(4-5):575-80.
Tanaka,S.,H.Kamitani,et al.(2000)."Preliminary individual adjuvant therapy for gliomas based on the results of molecular biological analyses for drug-resistance genes." J Neurooncol 46(2):157-71.
Tanaka,S.,I.Kobayashi,et al.(2001)."Drug-resistance gene expression and progression of astrocytic tumors." Brain Tumor Pathol 18(2):131-7.
Tew,K.D.and Z.Ronai(1999)."GST function in drug and stress response." Drug Resist Updat 2(3):143-147.
Theis,J.G.,H.S.Chan,et al.(2000)."Assessment of systemic toxicity in children receiving chemotherapy with cyclosporine for sarcoma." Med Pediatr Oncol 34(4):242-9.
Thevenod,F.,J.M.Friedmann,et al.(2000)."Up-regulation of multidmg resistance P-glycoprotein via nuclear factor-kappaB activation protects kidney proximal tubule cells from cadmiumand reactive oxygen species-induced apoptosis." J Biol Chem 275(3):1887-96.
Tosi,P.,G.Visani,et al.(1994)."Hydroxyurea enhances 3'-azido-3'-deoxythymidine(AZT)cytotoxicity in human chronic myeloid leukemia models." Eur J Haematol 52(5):291-5.
Trejo-Solis,C.,G.Palencia,et al.(2005)."Cas IIgly induces apoptosis in glioma C6 cells in vitro and in vivo through caspase-dependent and caspase-independent mechanisms." Neoplasia 7(6):563-74.
Tsuruo,T.,H.Iida,et al.(1981)."Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil." Cancer Res 41(5):1967-72.
Uchino,S.,M.Noguchi,et al.(1993)."p53 mutation in gastric cancer:a genetic model for carcinogenesis is common to gastric and colorectal cancer." Int J Cancer 54(5):759-64.
Vahrmeijer,A.L.,J.H.van Dierendonck,et al.(1999)."Potentiation of the cytostatic effect of melphalan on colorectal cancer hepatic metastases by infusion of buthionine sulfoximine (BSO) in the rat:enhanced tumor glutathione depletion by infusion of BSO in the hepatic artery." Cancer Chemother Pharmacol 44(2):111-6.
von Bossanyi,P.,S.Diete,et al.(1997)."Immunohistochemical expression of P-glycoprotein and glutathione S-transferases in cerebral gliomas and response to chemotherapy." Acta Neuropathol 94(6):605-11.
Vordermark,D.,K.Ruprecht,et al.(2006)."Glioblastoma multiforme with oligodendroglial component(GBMO):favorable outcome after post-operative radiotherapy and chemotherapy with nimustine(ACNU) and teniposide(VM26)." BMC Cancer 6:247.
Warmann,S.,M.Hunger,et al.(2002)."The role of the MDR1 gene in the development of multidrug resistance in human hepatoblastoma:clinical course and in vivo model." Cancer 95(8):1795-801.
Wedge,S.R.,J.K.Porteous,et al.(1996)."3-aminobenzamide and/or O6-benzylguanine evaluated as an adjuvant to temozolomide or BCNU treatment in cell lines of variable mismatch repair status and O6-alkylguanine-DNA alkyltransferase activity." Br J Cancer 74(7):1030-6.
Weller,M.,B.Muller,et al.(2003)."Neuro-Oncology Working Group 01 trial of nimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved-field radiotherapy in the first-line treatment of malignant glioma." J Clin Onco121(17):3276-84.
Westphal,M.,D.C.Hilt,et al.(2003)."A phase 3 trial of local chemotherapy with biodegradable carmustine(BCNU) wafers(Gliadel wafers) in patients with primary malignant glioma." Neuro Oncol 5(2):79-88.
Wijnhoven,S.W.,H.J.Kool,et al.(2001)."DMBA-induced toxic and mutagenic responses vary dramatically between NER-deficient Xpa,Xpc and Csb mice." Carcinogenesis 22(7):1099-106.
Wiman,K.G.(2007)."Restoration of Wild-Type p53 Function in Human Tumors:Strategies for Efficient Cancer Therapy." Adv Cancer Res 97:321-38.
Winter,S.,H.Strik,et al.(2000)."Glutathione S-transferase and drag sensitivity in malignant glioma." J Neurol Sci 179(S 1-2):115-21.
Wolff,J.E.,S.Berrak,et al.(2008)."Nitrosourea efficacy in high-grade glioma:a survival gain analysis summarizing 504 cohorts with 24193 patients." J Neurooncol 88(1):57-63.
Wong,R.P.,W.P.Tsang,et al.(2007)."p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3." Mol Cancer Ther 6(3):1054-61.
Wu,Z.N.,C.L.Chan,et al.(1992)."Expression of human O6-methylguanine-DNA methyltransferase in a DNA excision repair-deficient Chinese hamster ovary cell line and its response to certain alkylating agents." Cancer Res 52(1):32-5.
Xia,R.,G.Lin,et al.(1998)."[A study of the GSH contents,GST activity and the expression of GST isoenzyme and MRP in drug-resistant leukemic cell lines]." Zhonghua Xue Ye Xue Za Zhi 19(5):247-9.
Yamada,K.,Y.Ushio,et al.(1981)."[Changes of blood-brain barrier in the ethylnitrosourea induced rat glioma(author's transl)]." No To Shinkei 33(12):1251-5.
Yang,L.Q.,D.C.Fang,et al.(2004)."Effect of NF-kappaB,survivin,Bci-2 and Caspase3 on apoptosis of gastric cancer cells induced by tumor necrosis factor related apoptosis inducing ligand." World J Gastroenterol 10(1):22-5.
Yoshida,J.,T.Wakabayashi,et al.(1985)."[Combination therapy with HU IFN-beta and ACNU against malignant brain tumors,Part 1.Experimental study in vitro]." Gan To Kagaku Ryoho 12(1):99-104.
Yoshida,T.,K.Shimizu,et al.(1987)."[Possibility of overcoming ACNU resistance in ACNU-resistant sublines of rat brain tumors in vitro by a calmodulin inhibitor]." No Shinkei Geka 15(2):143-9.
Yoshida,T.,K.Shimizu,et al.(1987)."Modulation in vitro and in vivo of ACNU resistance in a subline of C6 glioma with reserpine." J Neurosurg 66(2):251-5.
Yu,Z.,J.Chen,et al.(1999)."Human DNA repair systems:an overview." Environ Mol Mutagen 33(1):3-20.
Zassler,B.,I.E.Blasig,et al.(2005)."Protein delivery of caspase-3 induces cell death in malignant C6 glioma,primary astrocytes and immortalized and primary brain capillary endothelial cells." J Neurooncol 71(2):127-34.
Zhang,J.P.,H.L.Shi,et al.(2006)."[Individualized chemotherapy based on drug sensitivity and resistance assay and MGMT protein expression for patients with malignant glioma--analysis of 42 cases]." Ai Zheng 25(12):1533-7.
Zhang,L.,D.Yu,et al.(2000)."Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression." Cancer Res 60(13):3655-61.
Zhao,Y.,N.Zhang,et al.(2006)."Tetrazolium violet induces G0/G1 arrest and apoptosis in brain tumor cells." J Neurooncol 77(2):109-15.
Zhao,Y.F.and Q.Z.Kong(2008)."Tetrazolium violet inhibits cell growth and induces cell death in C127 mouse breast tumor cells." Chem Biol Interact 174(1):19-26.
Zikan,V.,M.Semonsky,et al.(1979)."[Chemotherapy of malignant tumor growth.III.Substances with an alkylating effect]." Cesk Farm 28(2):62-81.
Znaidi,S.,S.Weber,et al.(2008)."Genomewide location analysis of Candida albicans Upc2p,a regulator of sterol metabolism and azole drug resistance." Eukaryot Cell 7(5):836-47.
朱春雷,张.,王运杰(2004].“亚甲蓝对C6细胞的促凋亡作用及其与BCNU协同抗肿瘤作用的研究.”且空瘟24(1):4.
李娜(2007).”盐酸小檗碱及联合应用顺铂诱导宫颈癌细胞株凋亡的研究.”佳木斯大学 硕士学位论文:53.
金澎,张.(2003).”MGMT反义RNA对人脑胶质瘤耐药性逆转的研究.”中国神经外科杂志 19:93-98.
郭建友,霍海如,姜廷良(2005).”衡量联合用药作用研究方法评价.”重要药理与临床 21(3):5.
傅相平,李安民(2008).”经颈动脉灌注ACNU与VM-26联合治疗复发性脑胶质瘤的临床研究.”Chinese Journal of Clinic Neurosurgery 13(3):168-169.
张翠(2006).“TV/O~6-BG与BCNU联合应用对小鼠乳腺癌细胞的抑制作用.”曲阜师范大学 硕士学位论文:37.
陈波,金.卢.(2004).”PKC抑制剂对MGC803细胞中P-gp的表达及耐药性的影响.”癌症 23(4):5.
马胜林,耿.(2001).”ACNU与Vm-26合用治疗脑瘤的实验研究.”Chinese Journal of Cancer 20(8):4.