胶质母细胞瘤诱导凋亡治疗及其机制研究
摘要
胶质母细胞瘤(glioblastoma,GBM)占颅内肿瘤的12-15％。该肿瘤的治疗方法主要是包括外科手术，它呈弥漫性浸润的生长特性限制了外科手术的发挥而不能达到真正意义上的完全切除，因此，术后放疗和化疗等辅助治疗对提高患者生存期具有重要意义。虽然近些年GBM的常规疗法(主要是手术切除和化学药物治疗)得以明显改良，其预后依然严峻，患者的平均术后寿命(或初次诊断后寿命)常不超过1年。胶质母细胞瘤在肿瘤形成过程中受一些功能失活的抑癌基因和一些过度激活的原癌基因的影响，瘤细胞生理状态的细胞凋亡和细胞周期的既有平衡遭到破坏。因此，深入研究开发基于诱导肿瘤细胞凋亡治疗的新型抗肿瘤药物是非常必要的。研究表明，天然药材中提取的皂甙类化合物是极富希望的。
ArdipusillosideI[3-O-(α-L-rhamnopyranosyl-(1→2)- -D-glucopyranosyl-(1→3)- (β-D-glucopyranosyl-(1→2))- -L-arabinopyranosyl)-cyclamiretin A]是从朱砂根(Ardisia pusilla A．DC，紫金牛科)中提取出来的具有抗炎症潜能的自然三萜五环皂苷。既往研究表明，ArdipusillosideI能够抑制多种肿瘤细胞的生长并诱导瘤细胞凋亡，包括宫颈腺癌细胞(HeLa细胞)，Lewis肺癌细胞和HepG2肝癌细胞，这表明该皂苷具有潜在的抗肿瘤特性；在Hela细胞中，细胞内游离钙的超载参与了它诱导肿瘤细胞凋亡的生化作用。
细胞凋亡，又称程序性细胞死亡，是一个高度保守，受机体严格控制的细胞自杀过程，是在许多不同的细胞内外生理事件调控下的清除衰老和突变细胞的正常生理功能。细胞凋亡存在两条途径，线粒体凋亡途径和死亡受体凋亡途径。线粒体途径的特点在于线粒体跨膜电位的去极化和细胞色素C的释放。死亡受体途径由Fas[肿瘤坏死因子(TNF)超家族的一种作用于细胞表面死亡受体的细胞因子]以及它的下游效应分子caspase-3的相继激活介导活化。Fas主要表达于肿瘤细胞表面作为受体介导细胞凋亡，其主要配体为FasL。Fas的细胞内结构域募集匹配分子如Fas相关死亡域(Fas-associatedDeath Domain，FADD)从而加快死亡诱导信号复合物(Death-inducingSignaling Complex，DISC)的形成。DISC形成后进一步募集Caspase-8前体并促进它们分子间的自发性裂解激活，从而活化的Caspase-8并激活下游的蛋白水解酶。在细胞凋亡过程中，各细胞器因为存在含天门冬氨酸的特殊位点而被众多活化的蛋白水解酶和核酸内(外)切酶靶向性水解，从而导致细胞发生凋亡特异性的生化和形态学改变。
在本研究中，我们观察了ArdipusillosideⅠ对胶质母细胞瘤细胞株U87MG细胞和原代培养的人源性胶质母细胞瘤细胞的诱导凋亡治疗作用，并探讨了其内在的效应机制。ArdipusillosideⅠ以时间和浓度依赖的方式显著抑制了瘤细胞的增殖活性，IC50大致相近，约4．05μM。ArdipusillosideⅠ治疗后的瘤细胞在显微镜下显示出明显的凋亡特征，包括染色质浓缩边集，细胞核分裂；这表明ArdipusillosideⅠ诱导了瘤细胞凋亡。ArdipusillosideⅠ治疗逐渐增加了两种胶质母细胞瘤细胞中处于亚G1细胞周期(凋亡期)的比例，并使瘤细胞周期阻滞于S期(DNA合成期)。此外，实验观察到ArdipusillosideⅠ增强了瘤细胞表面Fas受体及其配体FasL的表达，并激活Caspase-8和Caspase-3两大特异性蛋白水解酶。我们还注意到，随着FasL中和抗体的加入，Fas的激活被竞争性抑制之后，瘤细胞的凋亡率显著下降；而当我们用Caspase-8的特异性抑制剂z-IETD-fmk阻断了Caspase-8的激活之后，瘤细胞的凋亡几乎不受影响。这表明ArdipusillosideⅠ通过一种不依赖于Casepase-8的FasL/Fas信号介导的死亡受体途径诱导了瘤细胞的凋亡。上述结果表明，ArdipusillosideⅠ是一种能够诱导胶质母细胞瘤细胞凋亡的可靠的抗肿瘤药物。
我们的研究不仅证实了ArdipusillosideⅠ可以诱导U87MG细胞株和原代培养的胶质母细胞瘤株发生细胞凋亡的抗肿瘤作用，也明确了ArdipusillosideⅠ在治疗剂量窗内不会对非肿瘤性质的脑内大量存有的发挥支持细胞作用的胶质细胞SVGp12细胞株的生物活性和增殖构成危害我们用MTT法评估了ardipusillosideⅠ对人胶质母细胞瘤U87MG细胞、原代培养人源性胶质母细胞瘤和星形胶质SVGp12细胞的影响。统计结果表明ArdipusillosideⅠ以时间和浓度依赖的方式显著抑制了人胶质母细胞瘤U87MG细胞和原代培养人源性GBM细胞的增殖活性，与对照组相比，处理组瘤细胞OD值下降(P＜0．05)。ArdipusillosideⅠ并不影响代表脑内主要的支持细胞的星形胶质SVGp12细胞的活力，与对照组相比，处理组神经胶质细胞OD值无明显改变(P＞0．05)。这样，作为一种可望推向临床应用的化疗药物，ArdipusillosideⅠ的生物安全性得到了较大的保证。而我们所鉴定的ArdipusillosideⅠ通过一种不依赖于Casepase-8的FasL/Fas信号介导的死亡受体途径发挥抗肿瘤作用的分子机制又为我们开发针对相应效应分子的靶向性基因治疗药物提供了实验准备，从而更好地促进ArdipusillosideⅠ辅助药物的研发，完善该药物的临床应用方案。
Glioblastoma accounts for 12-15% of intracranial tumors. Effective treatmentis complicated by multiple factors, including the diffusely infiltrative nature ofthe disease, which limits complete surgical resection. Although conventionaltreatments have improved significantly, the prognosis for glioblastoma patients isgrim. Average life expectancy after initial diagnosis is usually no more than 1year. Glioblastoma carcinogenesis occurs following the functional inactivation ofseveral tumor suppressor genes with parallel activation of key oncogenes bymutations, which affect the apoptosis and cell cycle. Thus, intensive research hasbeen conducted to develop novel anticancer agents that induce cancer cellapoptosis. Saponins extracted from natural plants are among the most promising.
Ardipusilloside I [3-O-(α-L-rhamnopyranosyl-(1→2)- -D-glucopyranosyl-(1→3)-(β-D-glucopyranosyl-(1→2))- -L-arabinopyranosyl)-cyclamiretin A], anaturally occurring saponin with anti-inflammatory properties, is isolated fromArdisia pusilla A. DC, a member of the Myrsinaceae family. Primary studies in vivo and in vitro showed that ardipusilloside I inhibits the growth of, and inducesapoptosis in, human cervical adenocarcinoma cells (HeLa), Lewis pulmonarycarcinoma and hepatocarcinoma, demonstrating the potential anticancerproperties of this compound. The mechanisms by which these effects areachieved are not understood fully, although, in HeLa cells, they do involve anincrease of intracellular free calcium.
Apoptosis, or programmed cell death, is a highly conserved, tightly controlledcell suicide process that is regulated by many different intracellular andextracellular events to ablate neoplastic cells in normal physiological functions.Apoptosis is controlled by two potential pathways, the mitochondrial pathwayand the death receptor pathway. The mitochondrial pathway is characterized bythe loss of mitochondrial transmembrane potential and release of cytochrome c.The death receptor pathway is mediated by serial activation of Fas [a cell surfacedeath receptor of the tumor necrosis factor (TNF) family of cytokines] and theresultant effector caspase-3. Fas is a cell-surface receptor that mediates apoptoticcell death when triggered mainly by its lgand FasL. The intracellular domains ofFas recruit adapter molecules such as Fas-associated death domain (FADD), thusaccelerating the formation of a death-inducing signaling complex (DISC). DISCformation, in turn, recruits catalytically inactive procaspase-8 to allowintermolecular autocatalytic cleavage, thus releasing active caspase-8 to activatedownstream procaspases. During apoptosis process, cells are degraded by thecleavage of cellular substrates at specific sites containing aspartic acid and thenresult in the biochemical and morphological changes associated with apoptosisthrough the activation of proteases and endonucleases which catalyze key steps inthe death pathway.
Herein, we investigated its effect on glioblastoma cell line U87MG cells and primary cultured human glioblastoma cells, and examined the underlyingmechanism of action. Ardipusilloside I substantially decreased the number ofviable cells of both cell lines in a time- and concentration-dependent manner,with a similar IC_(50) of 4.05μM. Microscopy revealed apoptotic characteristics,including chromatin condensation and cell nucleus fragmentation, demonstratingthat ardipusilloside I induced apoptosis. Ardipusilloside I exposure also graduallyincreased the sub-G1 fraction (the apoptotic cell population) and an Sphase-arrest of both glioblastoma cells. Furthermore, ardipusilloside I increasedthe expression of Fas and its ligand (FasL), and enhanced the activation ofcaspase-8 and caspase-3. Additionally, we observed a significant decreasedapoptosis after the trigger effection of FasL was abolished by the neutralizationantibody anti-FasL antibody and an unchanged apoptosis level when theactivation of caspase-8 was interrupted by specific inhibitor z-lETD-fmk, whichsuggested that a casepase-8 independent FasL/Fas signaling mediated deathreceptor pathway is involved. These data suggested that ardipusilloside I could bedeveloped as a chemotherapeutic agent for the management of glioblatomas.
The current study not only confirms the induction of apoptosis byardipusilloside I in both glioblastoma U87MG cells and primary culturedglioblastoma cells, but also clearly demonstrates the minor effect ardipusilloside Iwith a concentration within the therapeutical dose-window has on the viability ofthe nonneoplastic astrocyte line SVGp12 which presented the supporting cellsthat are generously existed in brain parenchyma. The effect of ardipusilloside I onthe viability of U87MG cells, primary cultured glioblastoma cells and SVGp12astrocytes was assessed by the MTT assay. The number of viable U87MG cellsand primary cultured glioblastoma cells decreased significantly in aconcentration- and time-dependent manner compared to vehicle control cells. The OD value decreased compared to vehicle control cell.(p＜0.05). ButArdipusilloside I did not affect the viability of SVGp12 astrocytes whichpresented the supporting cells that are generously existed in brain parenchyma.The OD value did not alter compared with vehicle control cell(p＞0.05).
The biologic security of ardipusilloside I which is promising to be applied inthe clinical management for glioblastoma as a novel chemotherapeutic agent has beenapproved. Moreover, we investigated the role of FasL/Fas signaling mediateddeath receptor pathway in the chemotherapeutic effect of ardipusilloside I in vitro,which suggested an experimental base for developing targeting gene therapeuticagent that aims at specific effector factors. It is warranted that developingassistant agents for ardipusilloside I will consummate its clinical application.
ArdipusillosideI[3-O-(α-L-rhamnopyranosyl-(1→2)- -D-glucopyranosyl-(1→3)- (β-D-glucopyranosyl-(1→2))- -L-arabinopyranosyl)-cyclamiretin A]是从朱砂根(Ardisia pusilla A．DC，紫金牛科)中提取出来的具有抗炎症潜能的自然三萜五环皂苷。既往研究表明，ArdipusillosideI能够抑制多种肿瘤细胞的生长并诱导瘤细胞凋亡，包括宫颈腺癌细胞(HeLa细胞)，Lewis肺癌细胞和HepG2肝癌细胞，这表明该皂苷具有潜在的抗肿瘤特性；在Hela细胞中，细胞内游离钙的超载参与了它诱导肿瘤细胞凋亡的生化作用。
细胞凋亡，又称程序性细胞死亡，是一个高度保守，受机体严格控制的细胞自杀过程，是在许多不同的细胞内外生理事件调控下的清除衰老和突变细胞的正常生理功能。细胞凋亡存在两条途径，线粒体凋亡途径和死亡受体凋亡途径。线粒体途径的特点在于线粒体跨膜电位的去极化和细胞色素C的释放。死亡受体途径由Fas[肿瘤坏死因子(TNF)超家族的一种作用于细胞表面死亡受体的细胞因子]以及它的下游效应分子caspase-3的相继激活介导活化。Fas主要表达于肿瘤细胞表面作为受体介导细胞凋亡，其主要配体为FasL。Fas的细胞内结构域募集匹配分子如Fas相关死亡域(Fas-associatedDeath Domain，FADD)从而加快死亡诱导信号复合物(Death-inducingSignaling Complex，DISC)的形成。DISC形成后进一步募集Caspase-8前体并促进它们分子间的自发性裂解激活，从而活化的Caspase-8并激活下游的蛋白水解酶。在细胞凋亡过程中，各细胞器因为存在含天门冬氨酸的特殊位点而被众多活化的蛋白水解酶和核酸内(外)切酶靶向性水解，从而导致细胞发生凋亡特异性的生化和形态学改变。
在本研究中，我们观察了ArdipusillosideⅠ对胶质母细胞瘤细胞株U87MG细胞和原代培养的人源性胶质母细胞瘤细胞的诱导凋亡治疗作用，并探讨了其内在的效应机制。ArdipusillosideⅠ以时间和浓度依赖的方式显著抑制了瘤细胞的增殖活性，IC50大致相近，约4．05μM。ArdipusillosideⅠ治疗后的瘤细胞在显微镜下显示出明显的凋亡特征，包括染色质浓缩边集，细胞核分裂；这表明ArdipusillosideⅠ诱导了瘤细胞凋亡。ArdipusillosideⅠ治疗逐渐增加了两种胶质母细胞瘤细胞中处于亚G1细胞周期(凋亡期)的比例，并使瘤细胞周期阻滞于S期(DNA合成期)。此外，实验观察到ArdipusillosideⅠ增强了瘤细胞表面Fas受体及其配体FasL的表达，并激活Caspase-8和Caspase-3两大特异性蛋白水解酶。我们还注意到，随着FasL中和抗体的加入，Fas的激活被竞争性抑制之后，瘤细胞的凋亡率显著下降；而当我们用Caspase-8的特异性抑制剂z-IETD-fmk阻断了Caspase-8的激活之后，瘤细胞的凋亡几乎不受影响。这表明ArdipusillosideⅠ通过一种不依赖于Casepase-8的FasL/Fas信号介导的死亡受体途径诱导了瘤细胞的凋亡。上述结果表明，ArdipusillosideⅠ是一种能够诱导胶质母细胞瘤细胞凋亡的可靠的抗肿瘤药物。
我们的研究不仅证实了ArdipusillosideⅠ可以诱导U87MG细胞株和原代培养的胶质母细胞瘤株发生细胞凋亡的抗肿瘤作用，也明确了ArdipusillosideⅠ在治疗剂量窗内不会对非肿瘤性质的脑内大量存有的发挥支持细胞作用的胶质细胞SVGp12细胞株的生物活性和增殖构成危害我们用MTT法评估了ardipusillosideⅠ对人胶质母细胞瘤U87MG细胞、原代培养人源性胶质母细胞瘤和星形胶质SVGp12细胞的影响。统计结果表明ArdipusillosideⅠ以时间和浓度依赖的方式显著抑制了人胶质母细胞瘤U87MG细胞和原代培养人源性GBM细胞的增殖活性，与对照组相比，处理组瘤细胞OD值下降(P＜0．05)。ArdipusillosideⅠ并不影响代表脑内主要的支持细胞的星形胶质SVGp12细胞的活力，与对照组相比，处理组神经胶质细胞OD值无明显改变(P＞0．05)。这样，作为一种可望推向临床应用的化疗药物，ArdipusillosideⅠ的生物安全性得到了较大的保证。而我们所鉴定的ArdipusillosideⅠ通过一种不依赖于Casepase-8的FasL/Fas信号介导的死亡受体途径发挥抗肿瘤作用的分子机制又为我们开发针对相应效应分子的靶向性基因治疗药物提供了实验准备，从而更好地促进ArdipusillosideⅠ辅助药物的研发，完善该药物的临床应用方案。
Glioblastoma accounts for 12-15% of intracranial tumors. Effective treatmentis complicated by multiple factors, including the diffusely infiltrative nature ofthe disease, which limits complete surgical resection. Although conventionaltreatments have improved significantly, the prognosis for glioblastoma patients isgrim. Average life expectancy after initial diagnosis is usually no more than 1year. Glioblastoma carcinogenesis occurs following the functional inactivation ofseveral tumor suppressor genes with parallel activation of key oncogenes bymutations, which affect the apoptosis and cell cycle. Thus, intensive research hasbeen conducted to develop novel anticancer agents that induce cancer cellapoptosis. Saponins extracted from natural plants are among the most promising.
Ardipusilloside I [3-O-(α-L-rhamnopyranosyl-(1→2)- -D-glucopyranosyl-(1→3)-(β-D-glucopyranosyl-(1→2))- -L-arabinopyranosyl)-cyclamiretin A], anaturally occurring saponin with anti-inflammatory properties, is isolated fromArdisia pusilla A. DC, a member of the Myrsinaceae family. Primary studies in vivo and in vitro showed that ardipusilloside I inhibits the growth of, and inducesapoptosis in, human cervical adenocarcinoma cells (HeLa), Lewis pulmonarycarcinoma and hepatocarcinoma, demonstrating the potential anticancerproperties of this compound. The mechanisms by which these effects areachieved are not understood fully, although, in HeLa cells, they do involve anincrease of intracellular free calcium.
Apoptosis, or programmed cell death, is a highly conserved, tightly controlledcell suicide process that is regulated by many different intracellular andextracellular events to ablate neoplastic cells in normal physiological functions.Apoptosis is controlled by two potential pathways, the mitochondrial pathwayand the death receptor pathway. The mitochondrial pathway is characterized bythe loss of mitochondrial transmembrane potential and release of cytochrome c.The death receptor pathway is mediated by serial activation of Fas [a cell surfacedeath receptor of the tumor necrosis factor (TNF) family of cytokines] and theresultant effector caspase-3. Fas is a cell-surface receptor that mediates apoptoticcell death when triggered mainly by its lgand FasL. The intracellular domains ofFas recruit adapter molecules such as Fas-associated death domain (FADD), thusaccelerating the formation of a death-inducing signaling complex (DISC). DISCformation, in turn, recruits catalytically inactive procaspase-8 to allowintermolecular autocatalytic cleavage, thus releasing active caspase-8 to activatedownstream procaspases. During apoptosis process, cells are degraded by thecleavage of cellular substrates at specific sites containing aspartic acid and thenresult in the biochemical and morphological changes associated with apoptosisthrough the activation of proteases and endonucleases which catalyze key steps inthe death pathway.
Herein, we investigated its effect on glioblastoma cell line U87MG cells and primary cultured human glioblastoma cells, and examined the underlyingmechanism of action. Ardipusilloside I substantially decreased the number ofviable cells of both cell lines in a time- and concentration-dependent manner,with a similar IC_(50) of 4.05μM. Microscopy revealed apoptotic characteristics,including chromatin condensation and cell nucleus fragmentation, demonstratingthat ardipusilloside I induced apoptosis. Ardipusilloside I exposure also graduallyincreased the sub-G1 fraction (the apoptotic cell population) and an Sphase-arrest of both glioblastoma cells. Furthermore, ardipusilloside I increasedthe expression of Fas and its ligand (FasL), and enhanced the activation ofcaspase-8 and caspase-3. Additionally, we observed a significant decreasedapoptosis after the trigger effection of FasL was abolished by the neutralizationantibody anti-FasL antibody and an unchanged apoptosis level when theactivation of caspase-8 was interrupted by specific inhibitor z-lETD-fmk, whichsuggested that a casepase-8 independent FasL/Fas signaling mediated deathreceptor pathway is involved. These data suggested that ardipusilloside I could bedeveloped as a chemotherapeutic agent for the management of glioblatomas.
The current study not only confirms the induction of apoptosis byardipusilloside I in both glioblastoma U87MG cells and primary culturedglioblastoma cells, but also clearly demonstrates the minor effect ardipusilloside Iwith a concentration within the therapeutical dose-window has on the viability ofthe nonneoplastic astrocyte line SVGp12 which presented the supporting cellsthat are generously existed in brain parenchyma. The effect of ardipusilloside I onthe viability of U87MG cells, primary cultured glioblastoma cells and SVGp12astrocytes was assessed by the MTT assay. The number of viable U87MG cellsand primary cultured glioblastoma cells decreased significantly in aconcentration- and time-dependent manner compared to vehicle control cells. The OD value decreased compared to vehicle control cell.(p＜0.05). ButArdipusilloside I did not affect the viability of SVGp12 astrocytes whichpresented the supporting cells that are generously existed in brain parenchyma.The OD value did not alter compared with vehicle control cell(p＞0.05).
The biologic security of ardipusilloside I which is promising to be applied inthe clinical management for glioblastoma as a novel chemotherapeutic agent has beenapproved. Moreover, we investigated the role of FasL/Fas signaling mediateddeath receptor pathway in the chemotherapeutic effect of ardipusilloside I in vitro,which suggested an experimental base for developing targeting gene therapeuticagent that aims at specific effector factors. It is warranted that developingassistant agents for ardipusilloside I will consummate its clinical application.
引文
1.Louis DN, Ohgaki H, Wiestler OD, et al: The 2007 WHO classification of tumours of the central nervous system. Acta neuropathologica 2007,114:97-109
2.Nakazato Y: [The 4th Edition of WHO Classification of Tumours of the Central Nervous System published in 2007]. No shinkei geka 2008,36:473-491
3.Kita D, Yonekawa Y, Weller M, et al: PIK3CA alterations in primary (de novo) and secondary glioblastomas. Acta neuropathologica 2007,113:295-302
4.Knobbe CB, Trampe-Kieslich A, Reifenberger G: Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas. Neuropathology and applied neurobiology 2005, 31:486-490
5.Waite DC, Jacobson EW, Ennis FA, et al: Three double-blind, randomized trials evaluating the safety and tolerance of different formulations of the saponin adjuvant QS-21. Vaccine 2001, 19:3957-3967
6.Wang QF, Chen JC, Hsieh SJ, et al: Regulation of Bcl-2 family molecules and activation of caspase cascade involved in gypenosides-induced apoptosis in human hepatoma cells. Cancer letters 2002, 183:169-178
7.Yun TK: Experimental and epidemiological evidence on non-organ specific cancer preventive effect of Korean ginseng and identification of active compounds. Mutation research 2003, 523-524:63-74
8.Leung KW, Yung KK, Mak NK, et al: Neuroprotective effects of ginsenoside-Rgl in primary nigral neurons against rotenone toxicity.Neuropharmacology 2007, 52:827-835
9.Slovin SF, Ragupathi G, Musselli C, et al: Thomsen-Friedenreich (TF)antigen as a target for prostate cancer vaccine: clinical trial results with TF cluster (c)-KLH plus QS21 conjugate vaccine in patients with biochemically relapsed prostate cancer. Cancer Immunol Immunother 2005,54:694-702
10.Brenner C, Kroemer G: Apoptosis. Mitochondria-the death signal integrators. Science (New York, NY 2000, 289:1150-1151
11.Green DR, Reed JC: Mitochondria and apoptosis. Science 1998,281:1309-1312
12.Kluck RM, Bossy-Wetzel E, Green DR, et al: The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science(New York, NY 1997, 275:1132-1136
13.Yang J, Liu X, Bhalla K, et al: Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science (New York, NY 1997,275:1129-1132
14.Zhang QH, Wang XJ, Miao ZC, et al: [Studies on the saponin constituents of jiu jielong (Ardisea pusilla)]. Yao Xue Xue Bao 1993, 28:673-678
15.Tao X, Wang P, Yang X, et al: [Inhibitory effect of ardipusilloside-I on Lewis pulmonary carcinoma and hepatocarcinoma SMMC-7721]. Zhong Yao Cai 2005, 28:574-577
16.Hochberg FH, Pruitt A: Assumptions in the radiotherapy of glioblastoma.Neurology 1980, 30:907-911
17.Chang J, Thakur SB, Huang W, et al: Magnetic resonance spectroscopy imaging (MRSI) and brain functional magnetic resonance imaging (fMRI) for radiotherapy treatment planning of glioma. Technology in cancer research & treatment 2008, 7:349-362
18.Brandes AA, Tosoni A, Franceschi E, et al: Glioblastoma in adults. Critical reviews in oncology/hematology 2008, 67:139-152
19.Scott JN, Rewcastle NB, Brasher PM, et al: Long-term glioblastoma multiforme survivors: a population-based study. The Canadian journal of neurological sciences 1998, 25:197-201
20.Scott JN, Rewcastle NB, Brasher PM, et al: Which glioblastoma multiforme patient will become a long-term survivor? A population-based study.Annals of neurology 1999, 46:183-188
21.Shi WM, Wildrick DM, Sawaya R: Volumetric measurement of brain tumors from MR imaging. Journal of neuro oncology 1998, 37:87-93
22.Pollak L, Gur R, Walach N, et al: Clinical determinants of long-term survival in patients with glioblastoma multiforme. Tumori 1997,83:613-617
23.Bleehen NM, Stenning SP: A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Research Council Brain Tumour Working Party. British journal of cancer 1991, 64:769-774
24.Yuile P, Dent O, Cook R, et al: Survival of glioblastoma patients related to presenting symptoms, brain site and treatment variables. J Clin Neurosci 2006,13:747-751
25.Kiwit JC, Floeth FW, Bock WJ: Survival in malignant glioma: analysis of prognostic factors with special regard to cytoreductive surgery. Zentralblatt fur Neurochirurgie 1996, 57:76-88
26.Kelly PJ, Hunt C: The limited value of cytoreductive surgery in elderly patients with malignant gliomas. Neurosurgery 1994, 34:62-66; discussion 66-67
27.Sabbah P, Foehrenbach H, Dutertre G, et al: Multimodal anatomic,functional, and metabolic brain imaging for tumor resection. Clinical imaging 2002, 26:6-12
28.Warnke PC, Kreth FW, Ostertag CB: Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis.Neurosurgery 1995, 36:872-874
29.Albert FK, Forsting M, Sartor K, et al: Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis.Neurosurgery 1994, 34:45-60; discussion 60-41
30.Ammirati M, Vick N, Liao YL, et al: Effect of the extent of surgical resection on survival and quality of life in patients with supratentorial glioblastomas and anaplastic astrocytomas. Neurosurgery 1987, 21:201-206
31.Levin VA, Wara WM, Davis RL, et al: Phase Ⅲcomparison of BCNU and the combination of procarbazine, CCNU, and vincristine administered after radiotherapy with hydroxyurea for malignant gliomas. Journal of neurosurgery 1985, 63:218-223
32.Muto E, Shioyama Y, Nakamura K, et al: Adult rhabdomyosarcoma in the nasal and paranasal sinuses showing complete local response to a combination of chemotherapy and radiotherapy using 3D-CRT and EVIRT.Fukuoka igaku zasshi = Hukuoka acta medica 2005, 96:363-369
33.Stock M, Kroupa B, Georg D: Interpretation and evaluation of the gamma index and the gamma index angle for the verification of IMRT hybrid plans. Physics in medicine and biology 2005, 50:399-411
34.Ortiz de Urbina D, Santos M, Garcia-Berrocal I, et al: Intraoperative radiation therapy in malignant glioma: early clinical results. Neurological research 1995, 17:289-294
35.Sakai N, Yamada H, Andoh T, et al: Intraoperative radiation therapy for malignant glioma. Neurologia medico-chirurgica 1991, 31:702-707
36.Graham PH: Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 1993, 72:3367
37.Fine HA, Dear KB, Loeffler JS, et al: Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults.Cancer 1993, 71:2585-2597
38.Stewart LA: Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials.Lancet 2002, 359:1011-1018
39.Minniti G, De Sanctis V, Muni R, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients. Journal of neuro-oncology 2008, 88:97-103
40.Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England journal of medicine 2005, 352:987-996
41.Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. The New England journal of medicine2005, 352:997-1003
42.Weller M, Muller B, Koch R, et al: 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 Oncol 2003, 21:3276-3284
43.Brandes AA, Fiorentino MV: The role of chemotherapy in recurrent malignant gliomas: an overview. Cancer investigation 1996, 14:551-559
44.Wong ET, Hess KR, Gleason MJ, et al: Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase Ⅱclinical trials. J Clin Oncol 1999, 17:2572-2578
45.Yung WK, Prados MD, Yaya-Tur R, et al: Multicenter phase Ⅱtrial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol 1999, 17:2762-2771
46.Brada M, Hoang-Xuan K, Rampling R, et al: Multicenter phase Ⅱ trial of temozolomide in patients with glioblastoma multiforme at first relapse. Ann Oncol 2001, 12:259-266
47.Brandes AA, Ermani M, Basso U, et al: Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: a phase Ⅱ study. Oncology 2002, 63:38-41
48.Raff MC: Social controls on cell survival and cell death. Nature 1992,356:397-400
49.Walker NI, Harmon BV, Gobe GC, et al: Patterns of cell death. Methods and achievements in experimental pathology 1988, 13:18-54
50.Wyllie AH, Kerr JF, Currie AR: Cell death: the significance of apoptosis.International review of cytology 1980, 68:251-306
51.Raff MC, Barres BA, Burne JF, et al: Programmed cell death and the control of cell survival: lessons from the nervous system. Science (New York, NY 1993, 262:695-700
52.Cohen JJ, Duke RC, Fadok VA, et al: Apoptosis and programmed cell death in immunity. Annual review of immunology 1992, 10:267-293
53.Nagata S: Fas and Fas ligand: a death factor and its receptor. Advances in immunology 1994, 57:129-144
54.Nagata S, Suda T: Fas and Fas ligand: lpr and gld mutations. Immunology today 1995, 16:39-43
55.Trauth BC, Klas C, Peters AM, et al: Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science (New York, NY 1989,245:301-305
56.Yonehara S, Ishii A, Yonehara M: A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. The Journal of experimental medicine 1989,169:1747-1756
57.Itoh N, Yonehara S, Ishii A, et al: The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 1991,66:233-243
58.Oehm A, Behrmann I, Falk W, et al: Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Sequence identity with the Fas antigen. The Journal of biological chemistry 1992, 267:10709-10715
59.Watanabe-Fukunaga R, Brannan CI, Itoh N, et al: The cDNA structure,expression, and chromosomal assignment of the mouse Fas antigen. J Immunol 1992, 148:1274-1279
60.Smith CA, Farrah T, Goodwin RG: The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell 1994,76:959-962
61.Beutler B, van Huffel C: Unraveling function in the TNF ligand and receptor families. Science (New York, NY 1994, 264:667-668
62.Itoh N, Nagata S: A novel protein domain required for apoptosis.Mutational analysis of human Fas antigen. The Journal of biological chemistry 1993, 268:10932-10937
63.Tartaglia LA, Ayres TM, Wong GH, et al: A novel domain within the 55 kd TNF receptor signals cell death. Cell 1993, 74:845-853
64.Tartaglia LA, Rothe M, Hu YF, et al: Tumor necrosis factor's cytotoxic activity is signaled by the p55 TNF receptor. Cell 1993, 73:213-216
65.Inazawa J, Itoh N, Abe T, et al: Assignment of the human Fas antigen gene(Fas) to 10q24.1. Genomics 1992, 14:821-822
66.Lichter P, Walczak H, Weitz S, et al: The human APO-1 (APT) antigen maps to 10q23, a region that is syntenic with mouse chromosome 19.Genomics 1992, 14:179-180
67.Behrmann I, Walczak H, Krammer PH: Structure of the human APO-1 gene.European journal of immunology 1994, 24:3057-3062
68.Munsch D, Watanabe-Fukunaga R, Bourdon JC, et al: Human and mouse Fas (APO-1/CD95) death receptor genes each contain a p53-responsive element that is activated by p53 mutants unable to induce apoptosis. The Journal of biological chemistry 2000, 275:3867-3872
69.Ogasawara J, Watanabe-Fukunaga R, Adachi M, et al: Lethal effect of the anti Fas antibody in mice. Nature 1993, 364:806-809
70.Watanabe-Fukunaga R, Brannan CI, Copeland NG, et al:Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 1992, 356:314-317
71.Hulinska D, Krausova M, Janovska D, et al: Electron microscopy and the polymerase chain reaction of spirochetes from the blood of patients with Lyme disease. Central European journal of public health 1993, 1:81-85
72.Haas DA, Mailer C, Robinson BH: Using nitroxide spin labels. How to obtain Tle from continuous wave electron paramagnetic resonance spectra at all rotational rates. Biophysical journal 1993, 64:594-604
73.Takahashi T, Tanaka M, Inazawa J, et al: Human Fas ligand: gene structure,chromosomal location and species specificity. International immunology 1994,6:1567-1574
74.Takahashi T, Tanaka M, Brannan CI, et al: Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 1994,76:969-976
75.Yamamura T, Kondo T, Sakanaka S, et al: Analysis of T cell antigen receptors of myelin basic protein specific T cells in SJL/J mice demonstrates an alpha chain CDR3 motif associated with encephalitogenic T cells. International immunology 1994, 6:947-954
76.Suda T, Takahashi T, Golstein P, et al: Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 1993,75:1169-1178
77.Maeda H, Takata M, Takahashi S, et al: Adoptive transfer of a Th2-like cell line prolongs MHC class Ⅱ antigen disparate skin allograft survival in the mouse. International immunology 1994, 6:855-862
78.Lynch DH, Watson ML, Alderson MR, et al: The mouse Fas-ligand gene is mutated in gld mice and is part of a TNF family gene cluster. Immunity 1994, 1:131-136
79.Baumann A, Frings S, Godde M, et al: Primary structure and functional expression of a Drosophila cyclic nucleoti de-gated channel present in eyes and antennae. The EMBO journal 1994, 13:5040-5050
80.Baum PR, Gayle RB, 3rd, Ramsdell F, et al: Molecular characterization of murine and human OX40/OX40 ligand systems: identification of a human OX40 ligand as the HTLV-1-regulated protein gp34. The EMBO journal 1994, 13:3992-4001
81.Beckmann MP, Cerretti DP, Baum P, et al: Molecular characterization of a family of ligands for eph-related tyrosine kinase receptors. The EMBO journal 1994, 13:3757-3762
82.Baumgartner S, Martin D, Hagios C, et al: Tenm, a Drosophila gene related to tenascin, is a new pair-rule gene. The EMBO journal 1994,13:3728-3740
83.Anel A, Buferne M, Boyer C, et al: T cell receptor-induced Fas ligand expression in cytotoxic T lymphocyte clones is blocked by protein tyrosine kinase inhibitors and cyclosporin A. European journal of immunology 1994,24:2469-2476
84.Vignaux F, Vivier E, Malissen B, et al: TCR/CD3 coupling to Fas-based cytotoxicity. The Journal of experimental medicine 1995, 181:781-786
85.Suda T, Okazaki T, Naito Y, et al: Expression of the Fas ligand in cells of T cell lineage. J Immunol 1995, 154:3806-3813
86.Raff MC, Barres BA, Burne JF, et al: Programmed cell death and the control of cell survival. Philosophical transactions of the Royal Society of London 1994, 345:265-268
87.Jacobson MD, Burne JF, Raff MC: Mechanisms of programmed cell death and Bcl-2 protection. Biochemical Society transactions 1994, 22:600-602
88.Jacobson MD, Burne JF, Raff MC: Programmed cell death and Bcl-2 protection in the absence of a nucleus. The EMBO journal 1994,13:1899-1910
89.Lazebnik YA, Cole S, Cooke CA, et al: Nuclear events of apoptosis in vitro in cell-free mitotic extracts: a model system for analysis of the active phase of apoptosis. The Journal of cell biology 1993, 123:7-22
90.Newmeyer DD, Farschon DM, Reed JC: Cell-free apoptosis in Xenopus egg extracts: inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochondria. Cell 1994, 79:353-364
91.Ju ST, Cui H, Panka DJ, et al: Participation of target Fas protein in apoptosis pathway induced by CD4+ Th1 and CD8+ cytotoxic T cells.Proceedings of the National Academy of Sciences of the United States of America 1994, 91:4185-4189
92.Klas C, Debatin KM, Jonker RR, et al: Activation interferes with the APO 1 pathway in mature human T cells. International immunology 1993,5:625-630
93.Nunes J, Klasen S, Ragueneau M, et al: CD28 mAbs with distinct binding properties differ in their ability to induce T cell activation: analysis of early and late activation events. International immunology 1993, 5:311-315
94.Stalder T, Hahn S, Erb P: Fas antigen is the major target molecule for CD4+ T cell-mediated cytotoxicity. J Immunol 1994, 152:1127-1133
95.Miyawaki T, Uehara T, Nibu R, et al: Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J Immunol 1992, 149:3753-3758
96.Takahashi S, Sato N, Takayama S, et al: Establishment of apoptosis-inducing monoclonal antibody 2D1 and 2D1-resistant variants of human T cell lines. European journal of immunology 1993, 23:1935-1941
97.Wong GH, Goeddel DV: Fas antigen and p55 TNF receptor signal apoptosis through distinct pathways. J Immunol 1994, 152:1751-1755
98.Oltvai ZN, Korsmeyer SJ: Checkpoints of dueling dimers foil death wishes.Cell 1994,79:189-192
99.Kashiwabuchi N, Ikeda K, Araki K, et al: Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluR delta 2 mutant mice. Cell 1995, 81:245-252
100.Takayama S, Sato T, Krajewski S, et al: Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti-cell death activity. Cell 1995, 80:279-284
101.Hug H, Enari M, Nagata S: No requirement of reactive oxygen intermediates in Fas-mediated apoptosis. FEBS letters 1994, 351:311-313
102.Schulze-Osthoff K, Krammer PH, Droge W: Divergent signalling via APO 1/Fas and the TNF receptor, two homologous molecules involved in physiological cell death. The EMBO journal 1994, 13:4587-4596
103.Wiegmann K, Schutze S, Machleidt T, et al: Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling.Cell 1994,78:1005-1015
104.Clement MV, Stamenkovic I: Fas and tumor necrosis factor receptor-mediated cell death: similarities and distinctions. The Journal of experimental medicine 1994, 180:557-567
105.De Maria R, Cifone MG, Trotta R, et al: Triggering of human monocyte activation through CD69, a member of the natural killer cell gene complex family of signal transducing receptors. The Journal of experimental medicine 1994, 180:1999-2004
106.Cifone MG, De Maria R, Roncaioli P, et al: Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase. The Journal of experimental medicine 1994, 180:1547-1552
107.Chow LM, Jarvis C, Hu Q, et al: Ntk: a Csk-related protein-tyrosine kinase expressed in brain and T lymphocytes. Proceedings of the National Academy of Sciences of the United States of America 1994, 91:4975-4979
108.Jarvis WD, Kolesnick RN, Fornari FA, et al: Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway.Proceedings of the National Academy of Sciences of the United States of America 1994,91:73-77
109.Reed JC: Double identity for proteins of the Bcl-2 family. Nature 1997,387:773-776
110.Weller M, Malipiero U, Aguzzi A, et al: Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation. The Journal of clinical investigation 1995,95:2633-2643
111.Friedman HS, McLendon RE, Kerby T, et al: DNA mismatch repair and 06-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol 1998, 16:3851-3857
112.Silber JR, Bobola MS, Ghatan S, et al: 06-methylguanine-DNA methyltransferase activity in adult gliomas: relation to patient and tumor characteristics. Cancer research 1998, 58:1068-1073
113.Weller M: Predicting response to cancer chemotherapy: the role of p53.Cell and tissue research 1998, 292:435-445
114.Fulci G, Ishii N, Van Meir EG: p53 and brain tumors: from gene mutations to gene therapy. Brain pathology (Zurich, Switzerland) 1998, 8:599-613
115.Fueyo J, Gomez-Manzano C, Yung WK, et al: Suppression of human glioma growth by adenovirus-mediated Rb gene transfer. Neurology 1998, 50:1307-1315
116.Ueki K, Ono Y, Henson JW, et al: CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer research 1996,56:150-153
117.Furnari FB, Huang HJ, Cavenee WK: The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer research 1998, 58:5002-5008
118.Tamura M, Gu J, Takino T, et al: Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. Cancer research 1999, 59:442-449
119.Li DM, Sun H: PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces Gl cell cycle arrest in human glioblastoma cells. Proceedings of the National Academy of Sciences of the United States of America 1998,95:15406-15411
120.Maier D, Zhang Z, Taylor E, et al: Somatic deletion mapping on chromosome 10 and sequence analysis of PTEN/MMAC1 point to the 10q25-26 region as the primary target in low-grade and high-grade gliomas.Oncogene 1998, 16:3331-3335
121.Itoh N, Tsujimoto Y, Nagata S: Effect of bcl-2 on Fas antigen-mediated cell death. J Immunol 1993, 151:621-627
122.Pitti RM, Marsters SA, Lawrence DA, et al: Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 1998,396:699-703
123.Strand S, Hofmann WJ, Hug H, et al: Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells-a mechanism of immune evasion? Nature medicine 1996, 2:1361-1366
124.Nagata S: Fas ligand and immune evasion. Nature medicine 1996,2:1306-1307
125.Gratas C, Tohma Y, Van Meir EG, et al: Fas ligand expression in glioblastoma cell lines and primary astrocytic brain tumors. Brain pathology (Zurich, Switzerland) 1997, 7:863-869
126.Saas P, Walker PR, Hahne M, et al: Fas ligand expression by astrocytoma in vivo: maintaining immune privilege in the brain? The Journal of clinical investigation 1997, 99:1173-1178
127.Steinbach JP, Wolburg H, Klumpp A, et al: Hypoxia sensitizes human malignant glioma cells towards CD95L-induced cell death. Journal of neurochemistry 2005, 92:1340-1349
128.Wagenknecht B, Gulbins E, Lang F, et al: Lipoxygenase inhibitors block CD95 ligand-mediated apoptosis of human malignant glioma cells. FEBS letters 1997,409:17-23
129.Jekle A, Obst R, Lang F, et al: CD95/CD95 ligand-mediated counterattack does not block T cell cytotoxicity. Biochemical and biophysical research communications 2000, 272:395-399
130.Favre-Felix N, Fromentin A, Hammann A, et al: Cutting edge: the tumor counterattack hypothesis revisited: colon cancer cells do not induce T cell apoptosis via the Fas (CD95, APO-1) pathway. J Immunol 2000,164:5023-5027
131.O'Connell J, Bennett MW, O'Sullivan GC, et al: Resistance to Fas (APO-1/CD95)-mediated apoptosis and expression of Fas ligand in esophageal cancer: the Fas counterattack. Dis Esophagus 1999, 12:83-89
132.Leithauser F, Dhein J, Mechtersheimer G, et al: Constitutive and induced expression of APO-1, a new member of the nerve growth factor/tumor necrosis factor receptor superfamily, in normal and neoplastic cells.Laboratory investigation; a journal of technical methods and pathology 1993, 69:415-429
133.French LE, Hahne M, Viard I, et al: Fas and Fas ligand in embryos and adult mice: ligand expression in several immune-privileged tissues and coexpression in adult tissues characterized by apoptotic cell turnover. The Journal of cell biology 1996, 133:335-343
134.Richardson BC, Lalwani ND, Johnson KJ, et al: Fas ligation triggers apoptosis in macrophages but not endothelial cells. European journal of immunology 1994, 24:2640-2645
135.Weller M, Frei K, Groscurth P, et al: Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines. The Journal of clinical investigation 1994,94:954-964
136.Tachibana O, Nakazawa H, Lampe J, et al: Expression of Fas/APO-1 during the progression of astrocytomas. Cancer research 1995,55:5528-5530
137.Tohma Y, Gratas C, Van Meir EG, et al: Necrogenesis and Fas/APO-1(CD95) expression in primary (de novo) and secondary glioblastomas.Journal of neuropathology and experimental neurology 1998, 57:239-245
138.Roth W, Fontana A, Trepel M, et al: Immunochemotherapy of malignant glioma: synergistic activity of CD95 ligand and chemotherapeutics. Cancer Immunol Immunother 1997, 44:55-63
139.Kurimoto M, Nogami K, Ogiichi T, et al: Antiproliferative effect of multiple autocrine loop blockade in human malignant glioma cell lines.Neurologia medico-chirurgica 1995, 35:723-727
140.Weller M, Malipiero U, Rensing-Ehl A, et al: Fas/APO-1 gene transfer for human malignant glioma. Cancer research 1995, 55:2936-2944
141.Stanulla M, Welte K, Hadam MR, et al: Coexpression of stem cell factor and its receptor c-Kit in human malignant glioma cell lines. Acta neuropathologica 1995, 89:158-165
142.Roth W, Wagenknecht B, Grimmel C, et al: Taxol-mediated augmentation of CD95 ligand-induced apoptosis of human malignant glioma cells:association with bcl-2 phosphorylation but neither activation of p53 nor G2/M cell cycle arrest. British journal of cancer 1998, 77:404-411
143.Winter S, Roth W, Dichgans J, et al: Synergy of CD95 ligand and teniposide: no role of cleavable complex formation and enhanced CD95 expression. European journal of pharmacology 1998, 341:323-328
144.Winter S, Weller M: Potentiation of CD95L-induced apoptosis of human malignant glioma cells by topotecan involves inhibition of RNA synthesis but not changes in CD95 or CD95L protein expression. The Journal of pharmacology and experimental therapeutics 1998, 286:1374-1382
145.Weller M, Winter S, Schmidt C, et al: Topoisomerase-I inhibitors for human malignant glioma: differential modulation of p53, p21, bax and bcl-2 expression and of CD95-mediated apoptosis by camptothecin and beta-lapachone. International journal of cancer 1997, 73:707-714
146.Hueber A, Winter S, Weller M: Chemotherapy primes malignant glioma cells for CD95 ligand-induced apoptosis up-stream of caspase 3 activation.European journal of pharmacology 1998, 352:111-115
147.Micheau O, Solary E, Hammann A, et al: Sensitization of cancer cells treated with cytotoxic drugs to fas-mediated cytotoxicity. Journal of the National Cancer Institute 1997, 89:783-789
148.Muller M, Strand S, Hug H, et al: Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. The Journal of clinical investigation 1997,99:403-413
149.Friesen C, Herr I, Krammer PH, et al: Involvement of the CD95(APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nature medicine 1996, 2:574-577
150.Fulda S, Sieverts H, Friesen C, et al: The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells. Cancer research 1997, 57:3823-3829
151.Eischen CM, Kottke TJ, Martins LM, et al: Comparison of apoptosis in wild-type and Fas-resistant cells: chemotherapy-induced apoptosis is not dependent on Fas/Fas ligand interactions. Blood 1997, 90:935-943
152.Gamen S, Anel A, Lasierra P, et al: Doxorubicin-induced apoptosis in human T-cell leukemia is mediated by caspase-3 activation in a Fas-independent way. FEBS letters 1997, 417:360-364
153.Villunger A, Egle A, Kos M, et al: Drug-induced apoptosis is associated with enhanced Fas (Apo-1/CD95) ligand expression but occurs independently of Fas (Apo-1/CD95) signaling in human T-acute lymphatic leukemia cells. Cancer research 1997, 57:3331-3334
154.Rensing-Ehl A, Frei K, Flury R, et al: Local Fas/APO-1 (CD95)ligand-mediated tumor cell killing in vivo. Eur J Immunol 1995,25:2253-2258
155.Arai H, Gordon D, Nabel EG, et al: Gene transfer of Fas ligand induces tumor regression in vivo. Proc Natl Acad Sci U S A 1997, 94:13862-13867
156.Seino K, Kayagaki N, Okumura K, et al: Antitumor effect of locally produced CD95 ligand. Nat Med 1997, 3:165-170
157.Kondo S, Tanaka Y, Kondo Y, et al: Retroviral transfer of CPP32beta gene into malignant gliomas in vitro and in vivo. Cancer Res 1998, 58:962-967
158.Yu JS, Sena-Esteves M, Paulus W, et al: Retroviral delivery and tetracycline-dependent expression of IL-lbeta-converting enzyme (ICE) in a rat glioma model provides controlled induction of apoptotic death in tumor cells. Cancer Res 1996, 56:5423-5427
159.Kondo S, Ishizaka Y, Okada T, et al: FADD gene therapy for malignant gliomas in vitro and in vivo. Hum Gene Ther 1998, 9:1599-1608
160.Shirsat NV, Shaikh SA: Overexpression of the immediate early gene fra-1 inhibits proliferation, induces apoptosis, and reduces tumourigenicity of c6 glioma cells. Exp Cell Res 2003, 291:91-100
161.Grbovic O, Jovic V, Ruzdijic S, et al: 8-C1-cAMP affects glioma cell-cycle kinetics and selectively induces apoptosis. Cancer Invest 2002, 20:972-982
162.Chin LS, Murray SF, Zitnay KM, et al: K252a inhibits proliferation of glioma cells by blocking platelet-derived growth factor signal transduction.Clin Cancer Res 1997, 3:771-776
163.Chen TC, Wadsten P, Su S, et al: The type IV phosphodiesterase inhibitor rolipram induces expression of the cell cycle inhibitors p21(Cipl) and p27(Kip1), resulting in growth inhibition, increased differentiation, and subsequent apoptosis of malignant A-172 glioma cells. Cancer Biol Ther 2002, 1:268-276
164.Chen TC, Hinton DR, Zidovetzki R, et al: Up-regulation of the cAMP/PKA pathway inhibits proliferation, induces differentiation, and leads to apoptosis in malignant gliomas. Lab Invest 1998, 78:165-174
165.Dugan LL, Kim JS, Zhang Y, et al: Differential effects of cAMP in neurons and astrocytes. Role of B-raf. J Biol Chem 1999, 274:25842-25848
166.Wu Z, Tandon R, Ziembicki J, et al: Role of ceramide in Ca2+-sensing receptor-induced apoptosis. J Lipid Res 2005, 46:1396-1404
167.Mandil R, Ashkenazi E, Blass M, et al: Protein kinase Calpha and protein kinase Cdelta play opposite roles in the proliferation and apoptosis of glioma cells. Cancer Res 2001, 61:4612-4619
168.Klingler-Hoffmann M, Fodero-Tavoletti MT, Mishima K, et al: The protein tyrosine phosphatase TCPTP suppresses the tumorigenicity of glioblastoma cells expressing a mutant epidermal growth factor receptor. J Biol Chem 2001,276:46313-46318
169.Kolch W: Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 2000, 351 Pt 2:289-305
170.Noguchi K, Yamana H, Kitanaka C, et al: Differential role of the INK and p38 MAPK pathway in c-Myc- and s-Myc-mediated apoptosis. Biochem Biophys Res Commun 2000, 267:221-227
171.Kisseleva T, Bhattacharya S, Braunstein J, et al: Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 2002,285:1-24
172.Tachibana O, Lampe J, Kleihues P, et al: Preferential expression of Fas/APO1 (CD95) and apoptotic cell death in perinecrotic cells of glioblastoma multiforme. Acta Neuropathol 1996, 92:431-434
173.Hao C, Beguinot F, Condorelli G, et al: Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) mediated apotosis in human malignant glioma cells. Cancer Res 2001,61:1162-1170
174.Nagane M, Pan G, Weddle JJ, et al: Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res 2000, 60:847-853
175.Pan G, Ni J, Wei YF, et al: An antagonist decoy receptor and a death domain containing receptor for TRAIL. Science 1997, 277:815-818
176.Sheridan JP, Marsters SA, Pitti RM, et al: Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997,277:818-821
177.Kischkel FC, Lawrence DA, Chuntharapai A, et al:Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 2000, 12:611-620
178.Kagawa S, He C, Gu J, et al: Antitumor activity and bystander effects of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene.Cancer Res 2001, 61:3330-3338
179.Depraetere V, Golstein P: Dismantling in cell death: molecular mechanisms and relationship to caspase activation. Scand J Immunol 1998, 47:523-531
180.Tang HF, Yi YH, Li L, et al: Bioactive asterosaponins from the starfish Culcita novaeguineae. J Nat Prod 2005, 68:337-341
181.Tang HF, Yi YH, Li L, et al: Three new asterosaponins from the starfish Culcita novaeguineae and their bioactivity. Planta Med 2005, 71:458-463
182.Tang HF, Cheng G, Wu J, et al: Cytotoxic Asterosaponins Capable of Promoting Polymerization of Tubulin from the Starfish Culcita novaeguineae. J Nat Prod 2009
183.Tang HF, Yi YH, Li L, et al: Asterosaponins from the starfish Culcita novaeguineae and their bioactivities. Fitoterapia 2006, 77:28-34
184. Vichchatorn P, Wongkajornsilp A, Petvises S, et al: Dendritic cells pulsed with total tumor RNA for activation NK-like T cells against glioblastoma multiforme. J Neurooncol 2005, 75: 111-118
185. King GD, Curtin JF, Candolfi M, et al: Gene therapy and targeted toxins for glioma. Curr Gene Ther 2005, 5: 535-557
186．常洪波，章翔，甄海宁等．白藜芦醇抑制SHG 44胶质瘤细胞生长实验研究．[J]中华神经外科疾病研究杂志．2006；5(2)119-123
187．常洪波，章翔，甄海宁等．白藜芦醇诱导U87胶质瘤细胞凋亡及caspase-3的激活[J]中华神经医学杂志2006；5(4)：333-337
188．章微，费舟，章翔等．白藜芦醇抑制胶质瘤细胞生长与诱导细胞凋亡实验研究2004；3(5)：401-405
189. Cheng G, Zhang X, Tang HF, et al: Asterosaponin 1, a cytostatic compound from the starfish Culcita novaeguineae, functions by inducing apoptosis in human glioblastoma U87MG cells. J Neurooncol 2006, 79: 235-241
190. Zhang W, Fei Z, Zhen HN, et al: Resveratrol inhibits cell growth and induces apoptosis of rat C6 glioma cells. J Neurooncol 2007, 81: 231-240
191. Lin H, Zhang X, Cheng G, et al: Apoptosis induced by ardipusilloside Ⅲ through BAD dephosphorylation and cleavage in human glioblastoma U251MG cells. Apoptosis 2008, 13: 247-257
192．林洪，章翔，程光等．九节龙Ⅲ经BAD凋亡途径诱导胶质瘤U251细胞凋亡[J]．中华神经外科疾病研究杂志．2008；7(5)：431-435
193. Jung JI, Lim SS, Choi HJ, et al: Isoliquiritigenin induces apoptosis by depolarizing mitochondrial membranes in prostate cancer cells. J Nutr Biochem 2006, 17: 689-696
194. Kim BC, Mamura M, Choi KS, et al: Transforming growth factor beta 1 induces apoptosis through cleavage of BAD in a Smad3-dependent mechanism in FaO hepatoma cells. Mol Cell Biol 2002, 22:1369-1378
195.Ranta F, Avram D, Berchtold S, et al: Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. Diabetes 2006,55:1380-1390
196.Grethe S, Coltella N, Di Renzo MF, et al: p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis.Biochem Biophys Res Commun 2006, 347:781-790
197.Lee B, Galli S, Tsokos M: Sensitive Ewing sarcoma and neuroblastoma cell lines have increased levels of BAD expression and decreased levels of BAR expression compared to resistant cell lines. Cancer Lett 2007, 247:110-114
198.Bu L, Lephart ED: Soy isoflavones modulate the expression of BAD and neuron-specific beta Ⅲ tubulin in male rat brain. Neurosci Lett 2005,385:153-157
199.Ichinose M, Liu XH, Hagihara N, et al: Extracellular Bad fused to toxin transport domains induces apoptosis. Cancer Res 2002, 62:1433-1438
200.Li JL, Zhu JH, Jing ZZ, et al: [G-protein-coupled muscarinic acetylcholine receptor activation up-regulates Bcl-2 and phospho-bad via Ras-ERK 1/2 signaling pathway]. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao(Shanghai) 2003, 35:41-48
201.Korsmeyer SJ, Wei MC, Saito M, et al: Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 2000, 7:1166-1173
202.Condorelli F, Salomoni P, Cotteret S, et al: Caspase cleavage enhances the apoptosis-inducing effects of BAD. Mol Cell Biol 2001, 21:3025-3036
203.Yeh TC, Chiang PC, Li TK, et al: Genistein induces apoptosis in human hepatocellular carcinomas via interaction of endoplasmic reticulum stress and mitochondrial insult. Biochem Pharmacol 2007, 73:782-792
204.Kim HT, Kim BC, Kim IY, et al: Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis through cleavage of BAD in TSU-PR1 human cancer cells. J Biol Chem 2002, 277:32510-32515
205.F. Lefranc, V. Facchini and R. Kiss, Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas, Oncologist 12 (2007), pp. 1395-1403.
206.J.T. Isaacs, Role of programmed cell death in carcinogenesis, Environ.Health. Perspect. 101 (1993), pp. 27-33.
207.M. Nozaki, M. Tada, H. Kobayashi, C.L. Zhang, Y. Sawamura, H. Abe, N.Ishii and E.G. Van Meir, Roles of the functional loss of p53 and other genes in astrocytoma tumorigenesis and progression, Neuro. Oncol. 1 (1999),pp.124-137.
208.U. McDermott, D.B. Longley, L. Galligan, W. Allen, T. Wilson and P.G.Johnston, Effect of p53 status and STAT1 on chemotherapy-induced,Fas-mediated apoptosis in colorectal cancer, Cancer. Res. 65 (2005), pp.8951-8960.
209.D.S. Ziegler and A.L. Kung, Therapeutic targeting of apoptosis pathways in cancer, Curr. Opin. Oncol. 20 (2008), pp. 97-103.
210.D. Sulejczak, P. Grieb, M. Walski, M. Frontczak-Baniewicz, Apoptotic death of cortical neurons following surgical brain injury, Folia. Neuropathol.46 (2008), pp. 213-219.
211.V. Sharma, C. Joseph, S. Ghosh, A. Agarwal, M.K. Mishra and E. Sen,Kaempferol induces apoptosis in glioblastoma cells through oxidative stress,Mol. Cancer. Ther. 6 (2007), pp. 2544-2553.
212.I. Bantounas, C.P. Glover, S. Kelly, S. Iseki, L.A. Phylactou and J.B. Uney, Assessing adenoviral hammerhead ribozyme and small hairpin RNA cassettes in neurons: inhibition of endogenous caspase-3 activity and protection from apoptotic cell death, J. Neurosci. Res. 79 (2005), pp.661-669.
213.W. Li, S. Wang, C. Chen and G. Zhuang, Induction of tumor cell apoptosis via Fas/DR5, Cell. Mol. Immunol. 3 (2006), pp. 467-471.
214.D. Tang, J.M. Lahti and VJ. Kidd, Caspase-8 activation and bid cleavage contribute to MCF7 cellular execution in a caspase-3-dependent manner during staurosporine-mediated apoptosis, J. Biol. Chem. 275 (2000), pp.9303-9307.
215.X. Yang, R. Khosravi-Far, H.Y. Chang and D. Baltimore, Daxx, a novel Fas-binding protein that activates INK and apoptosis, Cell. 89 (1997), pp.1067-76.
216.N. Holler, R. Zaru, O. Micheau, M. Thome, A. Attinger, S. Valitutti, J.L.Bodmer, P. Schneider, B. Seed and I Tschopp, Fas triggers an alternative,caspase-8-independent cell death pathway using the kinase RIP as effector molecule, Nat. Immunol. 1 (2000), pp. 489-95.
217.I. Petak, R. Vernes, K.S. Szucs, M. Anozie, K. Izeradjene, L. Douglas, D.M. Tillman, D.C. Phillips and J.A. Houghton, A caspase-8-independent component in TRAIL/Apo-2L-induced cell death in human rhabdomyosarcoma cells, Cell. Death. Differ, 10 (2003), pp. 729-39.
218.H. Feng, Y. Zeng, M.W. Graner, L. Whitesell and E. Katsanis, Evidence for a Novel, Caspase-8-Independent, Fas Death Domain-Mediated Apoptotic Pathway, I Biomed. Biotechnol. 2004 (2004), pp. 41-51.
219.C.N. Mork, D.V. Faller and R.A. Spanjaard, A mechanistic approach to anticancer therapy: targeting the cell cycle with histone deacetylase inhibitors, Curr. Pharm. Des.11 (2005), pp. 1091-1104.
220. S.M. Meeran and S.K. Katiyar, Cell cycle control as a basis for cancer chemoprevention through dietary agents, Front. Biosci. 13 (2008), pp.2191-2202.
2.Nakazato Y: [The 4th Edition of WHO Classification of Tumours of the Central Nervous System published in 2007]. No shinkei geka 2008,36:473-491
3.Kita D, Yonekawa Y, Weller M, et al: PIK3CA alterations in primary (de novo) and secondary glioblastomas. Acta neuropathologica 2007,113:295-302
4.Knobbe CB, Trampe-Kieslich A, Reifenberger G: Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas. Neuropathology and applied neurobiology 2005, 31:486-490
5.Waite DC, Jacobson EW, Ennis FA, et al: Three double-blind, randomized trials evaluating the safety and tolerance of different formulations of the saponin adjuvant QS-21. Vaccine 2001, 19:3957-3967
6.Wang QF, Chen JC, Hsieh SJ, et al: Regulation of Bcl-2 family molecules and activation of caspase cascade involved in gypenosides-induced apoptosis in human hepatoma cells. Cancer letters 2002, 183:169-178
7.Yun TK: Experimental and epidemiological evidence on non-organ specific cancer preventive effect of Korean ginseng and identification of active compounds. Mutation research 2003, 523-524:63-74
8.Leung KW, Yung KK, Mak NK, et al: Neuroprotective effects of ginsenoside-Rgl in primary nigral neurons against rotenone toxicity.Neuropharmacology 2007, 52:827-835
9.Slovin SF, Ragupathi G, Musselli C, et al: Thomsen-Friedenreich (TF)antigen as a target for prostate cancer vaccine: clinical trial results with TF cluster (c)-KLH plus QS21 conjugate vaccine in patients with biochemically relapsed prostate cancer. Cancer Immunol Immunother 2005,54:694-702
10.Brenner C, Kroemer G: Apoptosis. Mitochondria-the death signal integrators. Science (New York, NY 2000, 289:1150-1151
11.Green DR, Reed JC: Mitochondria and apoptosis. Science 1998,281:1309-1312
12.Kluck RM, Bossy-Wetzel E, Green DR, et al: The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science(New York, NY 1997, 275:1132-1136
13.Yang J, Liu X, Bhalla K, et al: Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science (New York, NY 1997,275:1129-1132
14.Zhang QH, Wang XJ, Miao ZC, et al: [Studies on the saponin constituents of jiu jielong (Ardisea pusilla)]. Yao Xue Xue Bao 1993, 28:673-678
15.Tao X, Wang P, Yang X, et al: [Inhibitory effect of ardipusilloside-I on Lewis pulmonary carcinoma and hepatocarcinoma SMMC-7721]. Zhong Yao Cai 2005, 28:574-577
16.Hochberg FH, Pruitt A: Assumptions in the radiotherapy of glioblastoma.Neurology 1980, 30:907-911
17.Chang J, Thakur SB, Huang W, et al: Magnetic resonance spectroscopy imaging (MRSI) and brain functional magnetic resonance imaging (fMRI) for radiotherapy treatment planning of glioma. Technology in cancer research & treatment 2008, 7:349-362
18.Brandes AA, Tosoni A, Franceschi E, et al: Glioblastoma in adults. Critical reviews in oncology/hematology 2008, 67:139-152
19.Scott JN, Rewcastle NB, Brasher PM, et al: Long-term glioblastoma multiforme survivors: a population-based study. The Canadian journal of neurological sciences 1998, 25:197-201
20.Scott JN, Rewcastle NB, Brasher PM, et al: Which glioblastoma multiforme patient will become a long-term survivor? A population-based study.Annals of neurology 1999, 46:183-188
21.Shi WM, Wildrick DM, Sawaya R: Volumetric measurement of brain tumors from MR imaging. Journal of neuro oncology 1998, 37:87-93
22.Pollak L, Gur R, Walach N, et al: Clinical determinants of long-term survival in patients with glioblastoma multiforme. Tumori 1997,83:613-617
23.Bleehen NM, Stenning SP: A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Research Council Brain Tumour Working Party. British journal of cancer 1991, 64:769-774
24.Yuile P, Dent O, Cook R, et al: Survival of glioblastoma patients related to presenting symptoms, brain site and treatment variables. J Clin Neurosci 2006,13:747-751
25.Kiwit JC, Floeth FW, Bock WJ: Survival in malignant glioma: analysis of prognostic factors with special regard to cytoreductive surgery. Zentralblatt fur Neurochirurgie 1996, 57:76-88
26.Kelly PJ, Hunt C: The limited value of cytoreductive surgery in elderly patients with malignant gliomas. Neurosurgery 1994, 34:62-66; discussion 66-67
27.Sabbah P, Foehrenbach H, Dutertre G, et al: Multimodal anatomic,functional, and metabolic brain imaging for tumor resection. Clinical imaging 2002, 26:6-12
28.Warnke PC, Kreth FW, Ostertag CB: Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis.Neurosurgery 1995, 36:872-874
29.Albert FK, Forsting M, Sartor K, et al: Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis.Neurosurgery 1994, 34:45-60; discussion 60-41
30.Ammirati M, Vick N, Liao YL, et al: Effect of the extent of surgical resection on survival and quality of life in patients with supratentorial glioblastomas and anaplastic astrocytomas. Neurosurgery 1987, 21:201-206
31.Levin VA, Wara WM, Davis RL, et al: Phase Ⅲcomparison of BCNU and the combination of procarbazine, CCNU, and vincristine administered after radiotherapy with hydroxyurea for malignant gliomas. Journal of neurosurgery 1985, 63:218-223
32.Muto E, Shioyama Y, Nakamura K, et al: Adult rhabdomyosarcoma in the nasal and paranasal sinuses showing complete local response to a combination of chemotherapy and radiotherapy using 3D-CRT and EVIRT.Fukuoka igaku zasshi = Hukuoka acta medica 2005, 96:363-369
33.Stock M, Kroupa B, Georg D: Interpretation and evaluation of the gamma index and the gamma index angle for the verification of IMRT hybrid plans. Physics in medicine and biology 2005, 50:399-411
34.Ortiz de Urbina D, Santos M, Garcia-Berrocal I, et al: Intraoperative radiation therapy in malignant glioma: early clinical results. Neurological research 1995, 17:289-294
35.Sakai N, Yamada H, Andoh T, et al: Intraoperative radiation therapy for malignant glioma. Neurologia medico-chirurgica 1991, 31:702-707
36.Graham PH: Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 1993, 72:3367
37.Fine HA, Dear KB, Loeffler JS, et al: Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults.Cancer 1993, 71:2585-2597
38.Stewart LA: Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials.Lancet 2002, 359:1011-1018
39.Minniti G, De Sanctis V, Muni R, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients. Journal of neuro-oncology 2008, 88:97-103
40.Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England journal of medicine 2005, 352:987-996
41.Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. The New England journal of medicine2005, 352:997-1003
42.Weller M, Muller B, Koch R, et al: 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 Oncol 2003, 21:3276-3284
43.Brandes AA, Fiorentino MV: The role of chemotherapy in recurrent malignant gliomas: an overview. Cancer investigation 1996, 14:551-559
44.Wong ET, Hess KR, Gleason MJ, et al: Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase Ⅱclinical trials. J Clin Oncol 1999, 17:2572-2578
45.Yung WK, Prados MD, Yaya-Tur R, et al: Multicenter phase Ⅱtrial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol 1999, 17:2762-2771
46.Brada M, Hoang-Xuan K, Rampling R, et al: Multicenter phase Ⅱ trial of temozolomide in patients with glioblastoma multiforme at first relapse. Ann Oncol 2001, 12:259-266
47.Brandes AA, Ermani M, Basso U, et al: Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: a phase Ⅱ study. Oncology 2002, 63:38-41
48.Raff MC: Social controls on cell survival and cell death. Nature 1992,356:397-400
49.Walker NI, Harmon BV, Gobe GC, et al: Patterns of cell death. Methods and achievements in experimental pathology 1988, 13:18-54
50.Wyllie AH, Kerr JF, Currie AR: Cell death: the significance of apoptosis.International review of cytology 1980, 68:251-306
51.Raff MC, Barres BA, Burne JF, et al: Programmed cell death and the control of cell survival: lessons from the nervous system. Science (New York, NY 1993, 262:695-700
52.Cohen JJ, Duke RC, Fadok VA, et al: Apoptosis and programmed cell death in immunity. Annual review of immunology 1992, 10:267-293
53.Nagata S: Fas and Fas ligand: a death factor and its receptor. Advances in immunology 1994, 57:129-144
54.Nagata S, Suda T: Fas and Fas ligand: lpr and gld mutations. Immunology today 1995, 16:39-43
55.Trauth BC, Klas C, Peters AM, et al: Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science (New York, NY 1989,245:301-305
56.Yonehara S, Ishii A, Yonehara M: A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. The Journal of experimental medicine 1989,169:1747-1756
57.Itoh N, Yonehara S, Ishii A, et al: The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 1991,66:233-243
58.Oehm A, Behrmann I, Falk W, et al: Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Sequence identity with the Fas antigen. The Journal of biological chemistry 1992, 267:10709-10715
59.Watanabe-Fukunaga R, Brannan CI, Itoh N, et al: The cDNA structure,expression, and chromosomal assignment of the mouse Fas antigen. J Immunol 1992, 148:1274-1279
60.Smith CA, Farrah T, Goodwin RG: The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell 1994,76:959-962
61.Beutler B, van Huffel C: Unraveling function in the TNF ligand and receptor families. Science (New York, NY 1994, 264:667-668
62.Itoh N, Nagata S: A novel protein domain required for apoptosis.Mutational analysis of human Fas antigen. The Journal of biological chemistry 1993, 268:10932-10937
63.Tartaglia LA, Ayres TM, Wong GH, et al: A novel domain within the 55 kd TNF receptor signals cell death. Cell 1993, 74:845-853
64.Tartaglia LA, Rothe M, Hu YF, et al: Tumor necrosis factor's cytotoxic activity is signaled by the p55 TNF receptor. Cell 1993, 73:213-216
65.Inazawa J, Itoh N, Abe T, et al: Assignment of the human Fas antigen gene(Fas) to 10q24.1. Genomics 1992, 14:821-822
66.Lichter P, Walczak H, Weitz S, et al: The human APO-1 (APT) antigen maps to 10q23, a region that is syntenic with mouse chromosome 19.Genomics 1992, 14:179-180
67.Behrmann I, Walczak H, Krammer PH: Structure of the human APO-1 gene.European journal of immunology 1994, 24:3057-3062
68.Munsch D, Watanabe-Fukunaga R, Bourdon JC, et al: Human and mouse Fas (APO-1/CD95) death receptor genes each contain a p53-responsive element that is activated by p53 mutants unable to induce apoptosis. The Journal of biological chemistry 2000, 275:3867-3872
69.Ogasawara J, Watanabe-Fukunaga R, Adachi M, et al: Lethal effect of the anti Fas antibody in mice. Nature 1993, 364:806-809
70.Watanabe-Fukunaga R, Brannan CI, Copeland NG, et al:Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 1992, 356:314-317
71.Hulinska D, Krausova M, Janovska D, et al: Electron microscopy and the polymerase chain reaction of spirochetes from the blood of patients with Lyme disease. Central European journal of public health 1993, 1:81-85
72.Haas DA, Mailer C, Robinson BH: Using nitroxide spin labels. How to obtain Tle from continuous wave electron paramagnetic resonance spectra at all rotational rates. Biophysical journal 1993, 64:594-604
73.Takahashi T, Tanaka M, Inazawa J, et al: Human Fas ligand: gene structure,chromosomal location and species specificity. International immunology 1994,6:1567-1574
74.Takahashi T, Tanaka M, Brannan CI, et al: Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 1994,76:969-976
75.Yamamura T, Kondo T, Sakanaka S, et al: Analysis of T cell antigen receptors of myelin basic protein specific T cells in SJL/J mice demonstrates an alpha chain CDR3 motif associated with encephalitogenic T cells. International immunology 1994, 6:947-954
76.Suda T, Takahashi T, Golstein P, et al: Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 1993,75:1169-1178
77.Maeda H, Takata M, Takahashi S, et al: Adoptive transfer of a Th2-like cell line prolongs MHC class Ⅱ antigen disparate skin allograft survival in the mouse. International immunology 1994, 6:855-862
78.Lynch DH, Watson ML, Alderson MR, et al: The mouse Fas-ligand gene is mutated in gld mice and is part of a TNF family gene cluster. Immunity 1994, 1:131-136
79.Baumann A, Frings S, Godde M, et al: Primary structure and functional expression of a Drosophila cyclic nucleoti de-gated channel present in eyes and antennae. The EMBO journal 1994, 13:5040-5050
80.Baum PR, Gayle RB, 3rd, Ramsdell F, et al: Molecular characterization of murine and human OX40/OX40 ligand systems: identification of a human OX40 ligand as the HTLV-1-regulated protein gp34. The EMBO journal 1994, 13:3992-4001
81.Beckmann MP, Cerretti DP, Baum P, et al: Molecular characterization of a family of ligands for eph-related tyrosine kinase receptors. The EMBO journal 1994, 13:3757-3762
82.Baumgartner S, Martin D, Hagios C, et al: Tenm, a Drosophila gene related to tenascin, is a new pair-rule gene. The EMBO journal 1994,13:3728-3740
83.Anel A, Buferne M, Boyer C, et al: T cell receptor-induced Fas ligand expression in cytotoxic T lymphocyte clones is blocked by protein tyrosine kinase inhibitors and cyclosporin A. European journal of immunology 1994,24:2469-2476
84.Vignaux F, Vivier E, Malissen B, et al: TCR/CD3 coupling to Fas-based cytotoxicity. The Journal of experimental medicine 1995, 181:781-786
85.Suda T, Okazaki T, Naito Y, et al: Expression of the Fas ligand in cells of T cell lineage. J Immunol 1995, 154:3806-3813
86.Raff MC, Barres BA, Burne JF, et al: Programmed cell death and the control of cell survival. Philosophical transactions of the Royal Society of London 1994, 345:265-268
87.Jacobson MD, Burne JF, Raff MC: Mechanisms of programmed cell death and Bcl-2 protection. Biochemical Society transactions 1994, 22:600-602
88.Jacobson MD, Burne JF, Raff MC: Programmed cell death and Bcl-2 protection in the absence of a nucleus. The EMBO journal 1994,13:1899-1910
89.Lazebnik YA, Cole S, Cooke CA, et al: Nuclear events of apoptosis in vitro in cell-free mitotic extracts: a model system for analysis of the active phase of apoptosis. The Journal of cell biology 1993, 123:7-22
90.Newmeyer DD, Farschon DM, Reed JC: Cell-free apoptosis in Xenopus egg extracts: inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochondria. Cell 1994, 79:353-364
91.Ju ST, Cui H, Panka DJ, et al: Participation of target Fas protein in apoptosis pathway induced by CD4+ Th1 and CD8+ cytotoxic T cells.Proceedings of the National Academy of Sciences of the United States of America 1994, 91:4185-4189
92.Klas C, Debatin KM, Jonker RR, et al: Activation interferes with the APO 1 pathway in mature human T cells. International immunology 1993,5:625-630
93.Nunes J, Klasen S, Ragueneau M, et al: CD28 mAbs with distinct binding properties differ in their ability to induce T cell activation: analysis of early and late activation events. International immunology 1993, 5:311-315
94.Stalder T, Hahn S, Erb P: Fas antigen is the major target molecule for CD4+ T cell-mediated cytotoxicity. J Immunol 1994, 152:1127-1133
95.Miyawaki T, Uehara T, Nibu R, et al: Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J Immunol 1992, 149:3753-3758
96.Takahashi S, Sato N, Takayama S, et al: Establishment of apoptosis-inducing monoclonal antibody 2D1 and 2D1-resistant variants of human T cell lines. European journal of immunology 1993, 23:1935-1941
97.Wong GH, Goeddel DV: Fas antigen and p55 TNF receptor signal apoptosis through distinct pathways. J Immunol 1994, 152:1751-1755
98.Oltvai ZN, Korsmeyer SJ: Checkpoints of dueling dimers foil death wishes.Cell 1994,79:189-192
99.Kashiwabuchi N, Ikeda K, Araki K, et al: Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluR delta 2 mutant mice. Cell 1995, 81:245-252
100.Takayama S, Sato T, Krajewski S, et al: Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti-cell death activity. Cell 1995, 80:279-284
101.Hug H, Enari M, Nagata S: No requirement of reactive oxygen intermediates in Fas-mediated apoptosis. FEBS letters 1994, 351:311-313
102.Schulze-Osthoff K, Krammer PH, Droge W: Divergent signalling via APO 1/Fas and the TNF receptor, two homologous molecules involved in physiological cell death. The EMBO journal 1994, 13:4587-4596
103.Wiegmann K, Schutze S, Machleidt T, et al: Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling.Cell 1994,78:1005-1015
104.Clement MV, Stamenkovic I: Fas and tumor necrosis factor receptor-mediated cell death: similarities and distinctions. The Journal of experimental medicine 1994, 180:557-567
105.De Maria R, Cifone MG, Trotta R, et al: Triggering of human monocyte activation through CD69, a member of the natural killer cell gene complex family of signal transducing receptors. The Journal of experimental medicine 1994, 180:1999-2004
106.Cifone MG, De Maria R, Roncaioli P, et al: Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase. The Journal of experimental medicine 1994, 180:1547-1552
107.Chow LM, Jarvis C, Hu Q, et al: Ntk: a Csk-related protein-tyrosine kinase expressed in brain and T lymphocytes. Proceedings of the National Academy of Sciences of the United States of America 1994, 91:4975-4979
108.Jarvis WD, Kolesnick RN, Fornari FA, et al: Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway.Proceedings of the National Academy of Sciences of the United States of America 1994,91:73-77
109.Reed JC: Double identity for proteins of the Bcl-2 family. Nature 1997,387:773-776
110.Weller M, Malipiero U, Aguzzi A, et al: Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation. The Journal of clinical investigation 1995,95:2633-2643
111.Friedman HS, McLendon RE, Kerby T, et al: DNA mismatch repair and 06-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol 1998, 16:3851-3857
112.Silber JR, Bobola MS, Ghatan S, et al: 06-methylguanine-DNA methyltransferase activity in adult gliomas: relation to patient and tumor characteristics. Cancer research 1998, 58:1068-1073
113.Weller M: Predicting response to cancer chemotherapy: the role of p53.Cell and tissue research 1998, 292:435-445
114.Fulci G, Ishii N, Van Meir EG: p53 and brain tumors: from gene mutations to gene therapy. Brain pathology (Zurich, Switzerland) 1998, 8:599-613
115.Fueyo J, Gomez-Manzano C, Yung WK, et al: Suppression of human glioma growth by adenovirus-mediated Rb gene transfer. Neurology 1998, 50:1307-1315
116.Ueki K, Ono Y, Henson JW, et al: CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer research 1996,56:150-153
117.Furnari FB, Huang HJ, Cavenee WK: The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer research 1998, 58:5002-5008
118.Tamura M, Gu J, Takino T, et al: Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. Cancer research 1999, 59:442-449
119.Li DM, Sun H: PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces Gl cell cycle arrest in human glioblastoma cells. Proceedings of the National Academy of Sciences of the United States of America 1998,95:15406-15411
120.Maier D, Zhang Z, Taylor E, et al: Somatic deletion mapping on chromosome 10 and sequence analysis of PTEN/MMAC1 point to the 10q25-26 region as the primary target in low-grade and high-grade gliomas.Oncogene 1998, 16:3331-3335
121.Itoh N, Tsujimoto Y, Nagata S: Effect of bcl-2 on Fas antigen-mediated cell death. J Immunol 1993, 151:621-627
122.Pitti RM, Marsters SA, Lawrence DA, et al: Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 1998,396:699-703
123.Strand S, Hofmann WJ, Hug H, et al: Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells-a mechanism of immune evasion? Nature medicine 1996, 2:1361-1366
124.Nagata S: Fas ligand and immune evasion. Nature medicine 1996,2:1306-1307
125.Gratas C, Tohma Y, Van Meir EG, et al: Fas ligand expression in glioblastoma cell lines and primary astrocytic brain tumors. Brain pathology (Zurich, Switzerland) 1997, 7:863-869
126.Saas P, Walker PR, Hahne M, et al: Fas ligand expression by astrocytoma in vivo: maintaining immune privilege in the brain? The Journal of clinical investigation 1997, 99:1173-1178
127.Steinbach JP, Wolburg H, Klumpp A, et al: Hypoxia sensitizes human malignant glioma cells towards CD95L-induced cell death. Journal of neurochemistry 2005, 92:1340-1349
128.Wagenknecht B, Gulbins E, Lang F, et al: Lipoxygenase inhibitors block CD95 ligand-mediated apoptosis of human malignant glioma cells. FEBS letters 1997,409:17-23
129.Jekle A, Obst R, Lang F, et al: CD95/CD95 ligand-mediated counterattack does not block T cell cytotoxicity. Biochemical and biophysical research communications 2000, 272:395-399
130.Favre-Felix N, Fromentin A, Hammann A, et al: Cutting edge: the tumor counterattack hypothesis revisited: colon cancer cells do not induce T cell apoptosis via the Fas (CD95, APO-1) pathway. J Immunol 2000,164:5023-5027
131.O'Connell J, Bennett MW, O'Sullivan GC, et al: Resistance to Fas (APO-1/CD95)-mediated apoptosis and expression of Fas ligand in esophageal cancer: the Fas counterattack. Dis Esophagus 1999, 12:83-89
132.Leithauser F, Dhein J, Mechtersheimer G, et al: Constitutive and induced expression of APO-1, a new member of the nerve growth factor/tumor necrosis factor receptor superfamily, in normal and neoplastic cells.Laboratory investigation; a journal of technical methods and pathology 1993, 69:415-429
133.French LE, Hahne M, Viard I, et al: Fas and Fas ligand in embryos and adult mice: ligand expression in several immune-privileged tissues and coexpression in adult tissues characterized by apoptotic cell turnover. The Journal of cell biology 1996, 133:335-343
134.Richardson BC, Lalwani ND, Johnson KJ, et al: Fas ligation triggers apoptosis in macrophages but not endothelial cells. European journal of immunology 1994, 24:2640-2645
135.Weller M, Frei K, Groscurth P, et al: Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines. The Journal of clinical investigation 1994,94:954-964
136.Tachibana O, Nakazawa H, Lampe J, et al: Expression of Fas/APO-1 during the progression of astrocytomas. Cancer research 1995,55:5528-5530
137.Tohma Y, Gratas C, Van Meir EG, et al: Necrogenesis and Fas/APO-1(CD95) expression in primary (de novo) and secondary glioblastomas.Journal of neuropathology and experimental neurology 1998, 57:239-245
138.Roth W, Fontana A, Trepel M, et al: Immunochemotherapy of malignant glioma: synergistic activity of CD95 ligand and chemotherapeutics. Cancer Immunol Immunother 1997, 44:55-63
139.Kurimoto M, Nogami K, Ogiichi T, et al: Antiproliferative effect of multiple autocrine loop blockade in human malignant glioma cell lines.Neurologia medico-chirurgica 1995, 35:723-727
140.Weller M, Malipiero U, Rensing-Ehl A, et al: Fas/APO-1 gene transfer for human malignant glioma. Cancer research 1995, 55:2936-2944
141.Stanulla M, Welte K, Hadam MR, et al: Coexpression of stem cell factor and its receptor c-Kit in human malignant glioma cell lines. Acta neuropathologica 1995, 89:158-165
142.Roth W, Wagenknecht B, Grimmel C, et al: Taxol-mediated augmentation of CD95 ligand-induced apoptosis of human malignant glioma cells:association with bcl-2 phosphorylation but neither activation of p53 nor G2/M cell cycle arrest. British journal of cancer 1998, 77:404-411
143.Winter S, Roth W, Dichgans J, et al: Synergy of CD95 ligand and teniposide: no role of cleavable complex formation and enhanced CD95 expression. European journal of pharmacology 1998, 341:323-328
144.Winter S, Weller M: Potentiation of CD95L-induced apoptosis of human malignant glioma cells by topotecan involves inhibition of RNA synthesis but not changes in CD95 or CD95L protein expression. The Journal of pharmacology and experimental therapeutics 1998, 286:1374-1382
145.Weller M, Winter S, Schmidt C, et al: Topoisomerase-I inhibitors for human malignant glioma: differential modulation of p53, p21, bax and bcl-2 expression and of CD95-mediated apoptosis by camptothecin and beta-lapachone. International journal of cancer 1997, 73:707-714
146.Hueber A, Winter S, Weller M: Chemotherapy primes malignant glioma cells for CD95 ligand-induced apoptosis up-stream of caspase 3 activation.European journal of pharmacology 1998, 352:111-115
147.Micheau O, Solary E, Hammann A, et al: Sensitization of cancer cells treated with cytotoxic drugs to fas-mediated cytotoxicity. Journal of the National Cancer Institute 1997, 89:783-789
148.Muller M, Strand S, Hug H, et al: Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. The Journal of clinical investigation 1997,99:403-413
149.Friesen C, Herr I, Krammer PH, et al: Involvement of the CD95(APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nature medicine 1996, 2:574-577
150.Fulda S, Sieverts H, Friesen C, et al: The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells. Cancer research 1997, 57:3823-3829
151.Eischen CM, Kottke TJ, Martins LM, et al: Comparison of apoptosis in wild-type and Fas-resistant cells: chemotherapy-induced apoptosis is not dependent on Fas/Fas ligand interactions. Blood 1997, 90:935-943
152.Gamen S, Anel A, Lasierra P, et al: Doxorubicin-induced apoptosis in human T-cell leukemia is mediated by caspase-3 activation in a Fas-independent way. FEBS letters 1997, 417:360-364
153.Villunger A, Egle A, Kos M, et al: Drug-induced apoptosis is associated with enhanced Fas (Apo-1/CD95) ligand expression but occurs independently of Fas (Apo-1/CD95) signaling in human T-acute lymphatic leukemia cells. Cancer research 1997, 57:3331-3334
154.Rensing-Ehl A, Frei K, Flury R, et al: Local Fas/APO-1 (CD95)ligand-mediated tumor cell killing in vivo. Eur J Immunol 1995,25:2253-2258
155.Arai H, Gordon D, Nabel EG, et al: Gene transfer of Fas ligand induces tumor regression in vivo. Proc Natl Acad Sci U S A 1997, 94:13862-13867
156.Seino K, Kayagaki N, Okumura K, et al: Antitumor effect of locally produced CD95 ligand. Nat Med 1997, 3:165-170
157.Kondo S, Tanaka Y, Kondo Y, et al: Retroviral transfer of CPP32beta gene into malignant gliomas in vitro and in vivo. Cancer Res 1998, 58:962-967
158.Yu JS, Sena-Esteves M, Paulus W, et al: Retroviral delivery and tetracycline-dependent expression of IL-lbeta-converting enzyme (ICE) in a rat glioma model provides controlled induction of apoptotic death in tumor cells. Cancer Res 1996, 56:5423-5427
159.Kondo S, Ishizaka Y, Okada T, et al: FADD gene therapy for malignant gliomas in vitro and in vivo. Hum Gene Ther 1998, 9:1599-1608
160.Shirsat NV, Shaikh SA: Overexpression of the immediate early gene fra-1 inhibits proliferation, induces apoptosis, and reduces tumourigenicity of c6 glioma cells. Exp Cell Res 2003, 291:91-100
161.Grbovic O, Jovic V, Ruzdijic S, et al: 8-C1-cAMP affects glioma cell-cycle kinetics and selectively induces apoptosis. Cancer Invest 2002, 20:972-982
162.Chin LS, Murray SF, Zitnay KM, et al: K252a inhibits proliferation of glioma cells by blocking platelet-derived growth factor signal transduction.Clin Cancer Res 1997, 3:771-776
163.Chen TC, Wadsten P, Su S, et al: The type IV phosphodiesterase inhibitor rolipram induces expression of the cell cycle inhibitors p21(Cipl) and p27(Kip1), resulting in growth inhibition, increased differentiation, and subsequent apoptosis of malignant A-172 glioma cells. Cancer Biol Ther 2002, 1:268-276
164.Chen TC, Hinton DR, Zidovetzki R, et al: Up-regulation of the cAMP/PKA pathway inhibits proliferation, induces differentiation, and leads to apoptosis in malignant gliomas. Lab Invest 1998, 78:165-174
165.Dugan LL, Kim JS, Zhang Y, et al: Differential effects of cAMP in neurons and astrocytes. Role of B-raf. J Biol Chem 1999, 274:25842-25848
166.Wu Z, Tandon R, Ziembicki J, et al: Role of ceramide in Ca2+-sensing receptor-induced apoptosis. J Lipid Res 2005, 46:1396-1404
167.Mandil R, Ashkenazi E, Blass M, et al: Protein kinase Calpha and protein kinase Cdelta play opposite roles in the proliferation and apoptosis of glioma cells. Cancer Res 2001, 61:4612-4619
168.Klingler-Hoffmann M, Fodero-Tavoletti MT, Mishima K, et al: The protein tyrosine phosphatase TCPTP suppresses the tumorigenicity of glioblastoma cells expressing a mutant epidermal growth factor receptor. J Biol Chem 2001,276:46313-46318
169.Kolch W: Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 2000, 351 Pt 2:289-305
170.Noguchi K, Yamana H, Kitanaka C, et al: Differential role of the INK and p38 MAPK pathway in c-Myc- and s-Myc-mediated apoptosis. Biochem Biophys Res Commun 2000, 267:221-227
171.Kisseleva T, Bhattacharya S, Braunstein J, et al: Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 2002,285:1-24
172.Tachibana O, Lampe J, Kleihues P, et al: Preferential expression of Fas/APO1 (CD95) and apoptotic cell death in perinecrotic cells of glioblastoma multiforme. Acta Neuropathol 1996, 92:431-434
173.Hao C, Beguinot F, Condorelli G, et al: Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) mediated apotosis in human malignant glioma cells. Cancer Res 2001,61:1162-1170
174.Nagane M, Pan G, Weddle JJ, et al: Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res 2000, 60:847-853
175.Pan G, Ni J, Wei YF, et al: An antagonist decoy receptor and a death domain containing receptor for TRAIL. Science 1997, 277:815-818
176.Sheridan JP, Marsters SA, Pitti RM, et al: Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997,277:818-821
177.Kischkel FC, Lawrence DA, Chuntharapai A, et al:Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 2000, 12:611-620
178.Kagawa S, He C, Gu J, et al: Antitumor activity and bystander effects of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene.Cancer Res 2001, 61:3330-3338
179.Depraetere V, Golstein P: Dismantling in cell death: molecular mechanisms and relationship to caspase activation. Scand J Immunol 1998, 47:523-531
180.Tang HF, Yi YH, Li L, et al: Bioactive asterosaponins from the starfish Culcita novaeguineae. J Nat Prod 2005, 68:337-341
181.Tang HF, Yi YH, Li L, et al: Three new asterosaponins from the starfish Culcita novaeguineae and their bioactivity. Planta Med 2005, 71:458-463
182.Tang HF, Cheng G, Wu J, et al: Cytotoxic Asterosaponins Capable of Promoting Polymerization of Tubulin from the Starfish Culcita novaeguineae. J Nat Prod 2009
183.Tang HF, Yi YH, Li L, et al: Asterosaponins from the starfish Culcita novaeguineae and their bioactivities. Fitoterapia 2006, 77:28-34
184. Vichchatorn P, Wongkajornsilp A, Petvises S, et al: Dendritic cells pulsed with total tumor RNA for activation NK-like T cells against glioblastoma multiforme. J Neurooncol 2005, 75: 111-118
185. King GD, Curtin JF, Candolfi M, et al: Gene therapy and targeted toxins for glioma. Curr Gene Ther 2005, 5: 535-557
186．常洪波，章翔，甄海宁等．白藜芦醇抑制SHG 44胶质瘤细胞生长实验研究．[J]中华神经外科疾病研究杂志．2006；5(2)119-123
187．常洪波，章翔，甄海宁等．白藜芦醇诱导U87胶质瘤细胞凋亡及caspase-3的激活[J]中华神经医学杂志2006；5(4)：333-337
188．章微，费舟，章翔等．白藜芦醇抑制胶质瘤细胞生长与诱导细胞凋亡实验研究2004；3(5)：401-405
189. Cheng G, Zhang X, Tang HF, et al: Asterosaponin 1, a cytostatic compound from the starfish Culcita novaeguineae, functions by inducing apoptosis in human glioblastoma U87MG cells. J Neurooncol 2006, 79: 235-241
190. Zhang W, Fei Z, Zhen HN, et al: Resveratrol inhibits cell growth and induces apoptosis of rat C6 glioma cells. J Neurooncol 2007, 81: 231-240
191. Lin H, Zhang X, Cheng G, et al: Apoptosis induced by ardipusilloside Ⅲ through BAD dephosphorylation and cleavage in human glioblastoma U251MG cells. Apoptosis 2008, 13: 247-257
192．林洪，章翔，程光等．九节龙Ⅲ经BAD凋亡途径诱导胶质瘤U251细胞凋亡[J]．中华神经外科疾病研究杂志．2008；7(5)：431-435
193. Jung JI, Lim SS, Choi HJ, et al: Isoliquiritigenin induces apoptosis by depolarizing mitochondrial membranes in prostate cancer cells. J Nutr Biochem 2006, 17: 689-696
194. Kim BC, Mamura M, Choi KS, et al: Transforming growth factor beta 1 induces apoptosis through cleavage of BAD in a Smad3-dependent mechanism in FaO hepatoma cells. Mol Cell Biol 2002, 22:1369-1378
195.Ranta F, Avram D, Berchtold S, et al: Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. Diabetes 2006,55:1380-1390
196.Grethe S, Coltella N, Di Renzo MF, et al: p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis.Biochem Biophys Res Commun 2006, 347:781-790
197.Lee B, Galli S, Tsokos M: Sensitive Ewing sarcoma and neuroblastoma cell lines have increased levels of BAD expression and decreased levels of BAR expression compared to resistant cell lines. Cancer Lett 2007, 247:110-114
198.Bu L, Lephart ED: Soy isoflavones modulate the expression of BAD and neuron-specific beta Ⅲ tubulin in male rat brain. Neurosci Lett 2005,385:153-157
199.Ichinose M, Liu XH, Hagihara N, et al: Extracellular Bad fused to toxin transport domains induces apoptosis. Cancer Res 2002, 62:1433-1438
200.Li JL, Zhu JH, Jing ZZ, et al: [G-protein-coupled muscarinic acetylcholine receptor activation up-regulates Bcl-2 and phospho-bad via Ras-ERK 1/2 signaling pathway]. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao(Shanghai) 2003, 35:41-48
201.Korsmeyer SJ, Wei MC, Saito M, et al: Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 2000, 7:1166-1173
202.Condorelli F, Salomoni P, Cotteret S, et al: Caspase cleavage enhances the apoptosis-inducing effects of BAD. Mol Cell Biol 2001, 21:3025-3036
203.Yeh TC, Chiang PC, Li TK, et al: Genistein induces apoptosis in human hepatocellular carcinomas via interaction of endoplasmic reticulum stress and mitochondrial insult. Biochem Pharmacol 2007, 73:782-792
204.Kim HT, Kim BC, Kim IY, et al: Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis through cleavage of BAD in TSU-PR1 human cancer cells. J Biol Chem 2002, 277:32510-32515
205.F. Lefranc, V. Facchini and R. Kiss, Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas, Oncologist 12 (2007), pp. 1395-1403.
206.J.T. Isaacs, Role of programmed cell death in carcinogenesis, Environ.Health. Perspect. 101 (1993), pp. 27-33.
207.M. Nozaki, M. Tada, H. Kobayashi, C.L. Zhang, Y. Sawamura, H. Abe, N.Ishii and E.G. Van Meir, Roles of the functional loss of p53 and other genes in astrocytoma tumorigenesis and progression, Neuro. Oncol. 1 (1999),pp.124-137.
208.U. McDermott, D.B. Longley, L. Galligan, W. Allen, T. Wilson and P.G.Johnston, Effect of p53 status and STAT1 on chemotherapy-induced,Fas-mediated apoptosis in colorectal cancer, Cancer. Res. 65 (2005), pp.8951-8960.
209.D.S. Ziegler and A.L. Kung, Therapeutic targeting of apoptosis pathways in cancer, Curr. Opin. Oncol. 20 (2008), pp. 97-103.
210.D. Sulejczak, P. Grieb, M. Walski, M. Frontczak-Baniewicz, Apoptotic death of cortical neurons following surgical brain injury, Folia. Neuropathol.46 (2008), pp. 213-219.
211.V. Sharma, C. Joseph, S. Ghosh, A. Agarwal, M.K. Mishra and E. Sen,Kaempferol induces apoptosis in glioblastoma cells through oxidative stress,Mol. Cancer. Ther. 6 (2007), pp. 2544-2553.
212.I. Bantounas, C.P. Glover, S. Kelly, S. Iseki, L.A. Phylactou and J.B. Uney, Assessing adenoviral hammerhead ribozyme and small hairpin RNA cassettes in neurons: inhibition of endogenous caspase-3 activity and protection from apoptotic cell death, J. Neurosci. Res. 79 (2005), pp.661-669.
213.W. Li, S. Wang, C. Chen and G. Zhuang, Induction of tumor cell apoptosis via Fas/DR5, Cell. Mol. Immunol. 3 (2006), pp. 467-471.
214.D. Tang, J.M. Lahti and VJ. Kidd, Caspase-8 activation and bid cleavage contribute to MCF7 cellular execution in a caspase-3-dependent manner during staurosporine-mediated apoptosis, J. Biol. Chem. 275 (2000), pp.9303-9307.
215.X. Yang, R. Khosravi-Far, H.Y. Chang and D. Baltimore, Daxx, a novel Fas-binding protein that activates INK and apoptosis, Cell. 89 (1997), pp.1067-76.
216.N. Holler, R. Zaru, O. Micheau, M. Thome, A. Attinger, S. Valitutti, J.L.Bodmer, P. Schneider, B. Seed and I Tschopp, Fas triggers an alternative,caspase-8-independent cell death pathway using the kinase RIP as effector molecule, Nat. Immunol. 1 (2000), pp. 489-95.
217.I. Petak, R. Vernes, K.S. Szucs, M. Anozie, K. Izeradjene, L. Douglas, D.M. Tillman, D.C. Phillips and J.A. Houghton, A caspase-8-independent component in TRAIL/Apo-2L-induced cell death in human rhabdomyosarcoma cells, Cell. Death. Differ, 10 (2003), pp. 729-39.
218.H. Feng, Y. Zeng, M.W. Graner, L. Whitesell and E. Katsanis, Evidence for a Novel, Caspase-8-Independent, Fas Death Domain-Mediated Apoptotic Pathway, I Biomed. Biotechnol. 2004 (2004), pp. 41-51.
219.C.N. Mork, D.V. Faller and R.A. Spanjaard, A mechanistic approach to anticancer therapy: targeting the cell cycle with histone deacetylase inhibitors, Curr. Pharm. Des.11 (2005), pp. 1091-1104.
220. S.M. Meeran and S.K. Katiyar, Cell cycle control as a basis for cancer chemoprevention through dietary agents, Front. Biosci. 13 (2008), pp.2191-2202.