纳米羟基磷灰石诱导肝癌细胞死亡的作用靶点及机理研究
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摘要
纳米粒了是指尺寸在在1～100nm之间的颗粒材料,其独特的物理化学特性已
经引起了人们的极大研究兴趣。纳米技术是推动当今医学发展的主要动力之一,
在肿瘤防治方面的工作已成为目前研究的热点。
纳米羟基磷灰石抗肝癌的应用,得到了越来越多的关注。本课题选用均匀
沉淀法、溶胶-凝胶法制备了四种不同粒径的纳米羟基磷灰石,并应用激光粒度
分析仪、X-射线衍射、傅立叶红外光谱仪、透射电镜及其电子衍射技术对其粒
径、结晶度、成分、形貌等进行了表征。结果显示:纳米羟基磷灰石的粒径分
别是59.9nm、170.7nm、288.9nm和421.1nm;红外光谱测试含有羟基磷灰石的
特征吸收峰;随着粒径的逐渐增大,其结晶度越来越高,相应x-射线衍射的峰
值越尖锐;透射电镜观察分散性越差的颗粒,电子衍射环越清晰。
将制备的四种不同粒径的纳米羟基磷灰石,各以三种浓度通过MTT法进行
体外抗人肝癌细胞的筛选,结果显示,肝癌细胞对59.9nm的纳米羟基磷灰石高
度敏感,为非细胞毒介导的生长抑制效应,抑制率最高可达70%以上,面对人
肝细胞的抑制作用明显降低(P<0.01);肝癌细胞对l70.7nm纳米羟基磷灰石比较
敏感,但与前者(59.9nm)组比较具有显著性差异(P 时间测定、集落形成率测定和一般形态学观察,发现59.9nm的纳米羟基磷灰石
可使肝癌细胞的生长曲线上升缓慢,倍增时间延长,集落形成减少,这些变化
与纳米羟基磷灰石未处理纰比较都具有统汁学的差异(P 用不明显(P>0.05)。
首次采用透射电镜及其电子衍射技术定性研究了细胞内的纳米羟基磷灰石
成分,发现外源性的纳米羟基磷灰石能够进入细胞内,并且首次发现其定位于
内质网。进一步应用激光共聚焦显微镜技术定量检测了细胞内质网的变化,结
果显示:肝痛细胞的内质网含量低于肝细胞(P<0.01);肝癌痛细胞经纳米羟基磷灰
石作用后,内质网的含量降低(P<0.05),而肝细胞则变化不显著(P>0.05)。
应用琼脂糖凝胶电泳、流式细胞仪检测初步排除了肌癌细胞的凋亡,吖啶
橙荧光染色、透射电镜观察,首次提出肝癌细胞的死亡方式为非凋亡性程序性
死亡,而且与caspase-9的活性升高有关;进一步研究c-myc、p53的mRNA表
达,纳米羟基磷灰石抑制c-myc的表达、上调p53的表达,使肝癌细胞阻滞于
In recent years, there is a growing interest in nanoparticles (1~100nm) due to their physical and chemical characteristics. Nano-technology is one of the backbones that help to develop new medical treatment techniques, and much research work has been conducted focusing on the aspects of the prevention and treatment of tumors. The treatment of hepatocellular carcinoma with hydroxyapatite (HAP) nanoparticles has aroused much attention.In this study, four kinds of HAP nanoparticles with different sizes were prepared by the homogeneous precipitation and sol-gel method, and their size distribution, crystallization degree, components, and morphology were characterized by laser granularity instrument, X-ray diffraction, FT-IR spectrum, transmission electron microscope (TEM), and electron diffraction. The measured average particle sizes of the different HAP nanoparticles were 59.9nm, 170.7nm, 288.9nm, and 421.1nm. They also showed the characteristic absorbability peak of HAP. As the results revealed, increasing particle sizes leaded to higher crystallization degrees and X-radial diffraction peaks while smaller particle sizes resulted in clearer electron diffraction annuli.The prepared HAP nanoparticles were used for the treatment of hepatocellular carcinoma. The inhibition effect was determined in vitro for four different average particle sizes and three different concentrations by MTT assays. Furthermore, growth curve and time of double proliferation (T_D) tests, colony formation rate measurements, and morphology observations were conducted. The results showed that HAP nanoparticles with an average size of 59.9nm most effectively inhibited the proliferation of hepatocellular carcinoma cells with an inhibition rate of more than 70 percent, which was significantly higher than the effect of 170.7nm size HAP nanoparticles(P<0.01). The inhibition proliferation was free cytotoxicity-mediated However, the inhibition rate for hepatocytes was comparatively low (P<0.01). For the treatment of hepatocellular carcinoma cells with 59.9nm size HAP nanoparticles, the growth curve ascended slowly, the time of double proliferation prolonged, and clone
formed rarely, which were statistically different from the untreated group (P<0.05). However, there was no distinct effect on the hepatocytes (P>0.05).The components of HAP nanoparticles in cells were studied by the use of TEM and electron diffraction methods. The HAP nanoparticles were found entering the cells and locating in the endoplasmic reticulum. The changes of the cell endoplasmic reticulum treated with HAP nanoparticles were further examined with laser scanning confocal microscope. The results showed that the endoplasmic reticulum content in hepatocellular carcinoma cells was lower than that of the hepatocytes (P<0.01). After the treatment with HAP nanoparticles, the content of endoplasmic reticulum in hepatocellular carcinoma cells decreased (P<0.05), while that of hepatocytes did not change (P>0.05).The cause of the hepatocellular carcinoma cell death was paraptosis rather than apoptosis by agarose gel electrophoresis and flow cytometry. Further investigation of the activity of caspase-9 and the expression of mRNA of c-myc and p53 indicated that HAP particles arrest hepatocellular carcinoma cells at Gi phase by activating the caspase-9, inhibiting the expression of c-myc, and up-regulating the expression of p53.In short, HAP nanoparticles significantly inhibited the proliferation of hepatocellular carcinoma cells in vitro in comparison with that of hepatocytes (P<0.01). The inhibition mechanism can be described as the following: First, the HAP nanoparticle enter the cells and accumulate in the cell endoplasmic reticulum, where they affect the activity of caspase-9. By regulating the mRNA expression of c-myc, p53 , the proliferation of hepatocellular carcinoma cells is arrested at G| phase. As a result, the proliferation of hepatocellular carcinoma cells is inhibited, inducing them to paraptosis.
经引起了人们的极大研究兴趣。纳米技术是推动当今医学发展的主要动力之一,
在肿瘤防治方面的工作已成为目前研究的热点。
纳米羟基磷灰石抗肝癌的应用,得到了越来越多的关注。本课题选用均匀
沉淀法、溶胶-凝胶法制备了四种不同粒径的纳米羟基磷灰石,并应用激光粒度
分析仪、X-射线衍射、傅立叶红外光谱仪、透射电镜及其电子衍射技术对其粒
径、结晶度、成分、形貌等进行了表征。结果显示:纳米羟基磷灰石的粒径分
别是59.9nm、170.7nm、288.9nm和421.1nm;红外光谱测试含有羟基磷灰石的
特征吸收峰;随着粒径的逐渐增大,其结晶度越来越高,相应x-射线衍射的峰
值越尖锐;透射电镜观察分散性越差的颗粒,电子衍射环越清晰。
将制备的四种不同粒径的纳米羟基磷灰石,各以三种浓度通过MTT法进行
体外抗人肝癌细胞的筛选,结果显示,肝癌细胞对59.9nm的纳米羟基磷灰石高
度敏感,为非细胞毒介导的生长抑制效应,抑制率最高可达70%以上,面对人
肝细胞的抑制作用明显降低(P<0.01);肝癌细胞对l70.7nm纳米羟基磷灰石比较
敏感,但与前者(59.9nm)组比较具有显著性差异(P
可使肝癌细胞的生长曲线上升缓慢,倍增时间延长,集落形成减少,这些变化
与纳米羟基磷灰石未处理纰比较都具有统汁学的差异(P
首次采用透射电镜及其电子衍射技术定性研究了细胞内的纳米羟基磷灰石
成分,发现外源性的纳米羟基磷灰石能够进入细胞内,并且首次发现其定位于
内质网。进一步应用激光共聚焦显微镜技术定量检测了细胞内质网的变化,结
果显示:肝痛细胞的内质网含量低于肝细胞(P<0.01);肝癌痛细胞经纳米羟基磷灰
石作用后,内质网的含量降低(P<0.05),而肝细胞则变化不显著(P>0.05)。
应用琼脂糖凝胶电泳、流式细胞仪检测初步排除了肌癌细胞的凋亡,吖啶
橙荧光染色、透射电镜观察,首次提出肝癌细胞的死亡方式为非凋亡性程序性
死亡,而且与caspase-9的活性升高有关;进一步研究c-myc、p53的mRNA表
达,纳米羟基磷灰石抑制c-myc的表达、上调p53的表达,使肝癌细胞阻滞于
In recent years, there is a growing interest in nanoparticles (1~100nm) due to their physical and chemical characteristics. Nano-technology is one of the backbones that help to develop new medical treatment techniques, and much research work has been conducted focusing on the aspects of the prevention and treatment of tumors. The treatment of hepatocellular carcinoma with hydroxyapatite (HAP) nanoparticles has aroused much attention.In this study, four kinds of HAP nanoparticles with different sizes were prepared by the homogeneous precipitation and sol-gel method, and their size distribution, crystallization degree, components, and morphology were characterized by laser granularity instrument, X-ray diffraction, FT-IR spectrum, transmission electron microscope (TEM), and electron diffraction. The measured average particle sizes of the different HAP nanoparticles were 59.9nm, 170.7nm, 288.9nm, and 421.1nm. They also showed the characteristic absorbability peak of HAP. As the results revealed, increasing particle sizes leaded to higher crystallization degrees and X-radial diffraction peaks while smaller particle sizes resulted in clearer electron diffraction annuli.The prepared HAP nanoparticles were used for the treatment of hepatocellular carcinoma. The inhibition effect was determined in vitro for four different average particle sizes and three different concentrations by MTT assays. Furthermore, growth curve and time of double proliferation (T_D) tests, colony formation rate measurements, and morphology observations were conducted. The results showed that HAP nanoparticles with an average size of 59.9nm most effectively inhibited the proliferation of hepatocellular carcinoma cells with an inhibition rate of more than 70 percent, which was significantly higher than the effect of 170.7nm size HAP nanoparticles(P<0.01). The inhibition proliferation was free cytotoxicity-mediated However, the inhibition rate for hepatocytes was comparatively low (P<0.01). For the treatment of hepatocellular carcinoma cells with 59.9nm size HAP nanoparticles, the growth curve ascended slowly, the time of double proliferation prolonged, and clone
formed rarely, which were statistically different from the untreated group (P<0.05). However, there was no distinct effect on the hepatocytes (P>0.05).The components of HAP nanoparticles in cells were studied by the use of TEM and electron diffraction methods. The HAP nanoparticles were found entering the cells and locating in the endoplasmic reticulum. The changes of the cell endoplasmic reticulum treated with HAP nanoparticles were further examined with laser scanning confocal microscope. The results showed that the endoplasmic reticulum content in hepatocellular carcinoma cells was lower than that of the hepatocytes (P<0.01). After the treatment with HAP nanoparticles, the content of endoplasmic reticulum in hepatocellular carcinoma cells decreased (P<0.05), while that of hepatocytes did not change (P>0.05).The cause of the hepatocellular carcinoma cell death was paraptosis rather than apoptosis by agarose gel electrophoresis and flow cytometry. Further investigation of the activity of caspase-9 and the expression of mRNA of c-myc and p53 indicated that HAP particles arrest hepatocellular carcinoma cells at Gi phase by activating the caspase-9, inhibiting the expression of c-myc, and up-regulating the expression of p53.In short, HAP nanoparticles significantly inhibited the proliferation of hepatocellular carcinoma cells in vitro in comparison with that of hepatocytes (P<0.01). The inhibition mechanism can be described as the following: First, the HAP nanoparticle enter the cells and accumulate in the cell endoplasmic reticulum, where they affect the activity of caspase-9. By regulating the mRNA expression of c-myc, p53 , the proliferation of hepatocellular carcinoma cells is arrested at G| phase. As a result, the proliferation of hepatocellular carcinoma cells is inhibited, inducing them to paraptosis.
引文
[1] 张立德,牟季美.纳米材料学.沈阳:辽宁科学技术出版社.1994.1～111
[2] 薛群基,徐康.纳米化学.化学进展,2000.12(4):431～444
[3] 张志昆,崔作林.纳米技术与纳米材料.北京:国防工业出版社,2000.10
[4] 解思深,张立德.创新者的报告之纳米科学与技术研究成果专著.北京:科学出版社,2000.12
[5] 王宏飞.美国启动《癌症纳米技术计划》.全球科技经济瞭望,2004.12:4～5
[6] 中国康凯信息咨询公司.中国纳米技术行业研究报告.2005.3
[7] Clark LC, Ddalkin B, Krongrad A, et al. Decreased incidence of prostate cancer with selenium supplementation: results of a double-bilnd cancer prevention trial. Br J Urol,1998.81 (5):730～4
[8] Patterson BH, Levander OA. Naturally occurring selenium compounds in cancer chemoprevention trials:a workshop summary. Cancer Epidemiol Biomarkers Prey, 1997.6(1):63～9
[9] Combs GF Jr, Clark LC, Turnbull B W. Reduction of cancer mortality and incidence by selenium supplementation. Med Klin,1997.92(Suppl 3):42～45
[10] Bronzetti G, della Croce C. Selenium: its important roles in life and contrasting aspects. J Environ Patho Toxicol Oncol,1993.12(2):59～71
[11] Gao Xueyun, Zhang Jinsong, Zhang Lide. Hollow sphere selenium nanoparticles: their In-Vitro Anti Hydroxyl Radical Effect. Adv Mater,2002.14(4):290～293
[12] 朱茂祥,张松,杨陟华,等.纳米硒对 4-甲基硝胺-1-(3-吡啶)-1-丁酮诱发昆明小鼠肺癌的防治研究.癌症,2000.19(10):883
[13] Yi DK, Kim DY. Polymer nanosphere lithography: fabrication of an ordered trigonal polymeric nanostructure. Chem Commun (Camb),2003.21:982～983
[14] Labhasetwar V, Song C. Nanoparticle drug delivery system for restenosis. Advanced Drug alivery Reviews, 1997.24:63～86
[15] Allcock H R, Pucker S R. Poly((amino acid ester) phosphazenes) as substrates for the controlled release of small molecules. Biomaterials, 1994.15:563
[16] Fu K, Griebenow K, Hsieh L, et al. FT-IR characterization of the secondary structure of proteins encapsulated within PLGA microspheres. J Controlled Release, 1999.58:357～369
[17] Taylor J R, Fang M M, Nie S M A. Probing specific sequences in single DNA molecule with bioconjugated fluorescent nanoparticles. Chemistry,2000. 72(9):1979～1986
[18] Cleland L, Jobnson J. Recombinant human growth hormonepoly(lactic-co-glycolic acid) microsphere formulation development. Advanced Drug Delivery Reviews, 1998.28:71～84
[19] Mattson M P, Haddon R C, Rao A M. Molecular functionalization of carbon nanotubes and use as substrates for neuronal growth. J Mol Nurosci,2000.14:175～82
[20] Haynes C L, Van Dayne R P. Nanosphere lithograpby. J Plays Chem(B),2001.105:5599～5611
[21] Chen X Y, Li J R. Thromboxane A2 regulation of endothelial cell migration, angiogenesis, and tumor matestasis. Biochem & Biophys Res Commun, 1998.245:352
[22] Storhoff J J, Elghanian R, Mucic R C J. One-pot colorimetric differentiation of polynucleotides with single base imperfections using gold nanoparticle pbobles. Am Chem Soc, 1998. 120:195
[23] Lin L, Zhao H Q. Receptor activity. Biochem & Biophys Res Commun,2000.274:817
[24] Bruchez J. Semiconduct nanocrystals as fluorescent biological labels. Science, 1998.281:2031～2033
[25] Lacoste E. Super-resolution molecular ruler using single quantum dots. J Biophysics,2000.78:402A
[26] 贺达仁,谢嘉平.影响21世纪医学进程的纳米技术.医学与哲学,2000.21(2):31～32
[27] Silva GA. Introduction to nanotechnology and its applicalions to medicine. Surg Neurol,2004.61:216～220
[28] Lewin M, Carlesso N, Tung CH, et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat Biotechnol,2000.18:410～414
[29] 秦仁义,裘法祖.纳米生物技术在实验外科的应用前景.中华实验外科杂志,2003.20:773～775
[30] Tiefenauer LX, Tschirky A, KKne G, et al.. Invivo evaluation of magnetite nanoparticles for use as a tumor contrast agent in MRI. Magn Reson Imaging,1996.14(4):391～394
[31] 陈丽英.中国率先应用纳米技术诊断肝癌.中国新药杂志,2004.13(6):564
[32] Jordan A. Nanotechnology and consequences for surgical oncology. Kongressbd Dtsch Ges Chir Kongr,2002.119:821～828
[33] Majeti V J. Nano and microparticles as controlled drug delivery devices. Pharm Pharmaceut Sci, 2000.3:234～258
[34] Labhasetwar V, Chen B, Muller M. Gene-based therapies for restenosis and others source. Advanced Drug Delivery Reviews, 1997. 24: 109～122
[35] Griffith L. Polymer biomaterials. Materialia, 2000. 48:263～277
[36] Peppas A. Drug diffusion and binding in ionizable interpenetrating networks from poly(vinyl alcohol) and poly(acrylic acid). Eru J Pharm Biopharm, 1998. 46(1):15～30
[37] Cleland L. Solvent evaporation processes for the production of controlled release biodegradable microsphere formulations for therapeutics and vaccines. Biotechnology Progress, 1998.14:102-107
[38] Rajaram C. Electrochemical and spectroscopic characterization of self-assembled monolayers of ferrocenylalkyl compounds with amide linkages. J Surfaces and Colloids,1998.14:124~136
[39] Dubois J C, Exbrayat P, Couble M L, et al. Effect of new machinable ceramic on behavior of rat bone cells cultured in vitro. J Biomed Mater Res, 1998.43:215-225
[40] Hanes J, Cleland L. New advances in microsphere-based single-dose vaccines. Advanced Drug Delivery Reviews,1998.28:97~120
[41] Garrett Q, Chatelier C. Effect of charged groups on the adsorption and penetration of proteins onto and into carboxymethylated poly(HEMA)hydrogels. Biomaterials, 1998.19:2175-2183
[42] Black J. Biological performance of materials:fundamentals of biocompatibility. New York:Marcell Dekker Inc, 1992.25-109
[43] Kwon S. Polymeric micelles as new drug carriers. Advanced Drug Delivery Reviews,1996.21:107~125
[44] Dunn E, Coombes A G A. In vitro cell interaction and in vivo biodistribution of poly( lactide-co-glycolide) nanospheres surface modified by poloxamer and poloxamine copolymers. J Controlled Release, 1997.44:65-71
[45] Langer R. Drug delivery and targeting- The design of degradable materials and the development of intelligent delivery systems have had an enormous impact on drug-based therapies. Nature, 1998.392:5-9
[46] Na K, Park KH, Kim SW, et al. Self-assembled hydrogel nanoparticles from curdlan derivatives: characterization, anti-cancer drug release and interaction with a hepatoma cell (HepG2). J Controlled Release,2000.699:225~236
[47] Na K, Bum Lee T, Park KH, et al. Self-assembled nanoparticles of hydrophobically modified polysaccharide bearing vitamin H as a targeted anti-cancer drug delivery system. Eur J Pharm Sci,2003.18(2): 165-173
[48] Mao HQ, Roy K, Troung-Le VL, et al. Chitosan-DNA nanoparticles as gene carriers: synthesis, characterization and transfection efficiency. J Control Releasc,2001.70:399-421
[49] Ito A, Matsuoka F, Honda H, et al. Antitumor effects of combined therapy of recombinant heat shock protein 70 and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma. Cancer Immunol Immunother,2004.53:26~32
[50] Eichman JD, Bielinska AU, Kukowska-Latallo JF, et al. The use of PAMAM dendrimers in
the efficient transfer of genetic material into cells. Pharm Sci Technol Today,2000.3:232～245
[51] Reynolds AR, Moein Moghimi S, Hodivala-Dilke K. Nanoparticle-mediated gene delivery to tumour neovaseulature. Trends Mol Med,2003.9:2～4
[52] KRISHNA R, MAYER LD. Multidrug resistance(MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci,2000. 11(4):265～283
[53] SOMA CE, DUBERNET C, BENTOLILA D, et al. Reversion of multidrug resistance by co-encapsulation of doxorubicin and cyclosporin A in polyalkylcyanoacrylate nanoparticles. Bio materials,2000.21 (1): 1～7
[54] Vandorpe J, Schacht E. Poly(organo phosphazene) nanoparticles surface modified with poly(ethylene oxide). Biotechnology and Bioengineering, 1996.52:89～95
[55] Samsavar L. Dual stage instrument for scanning a specimen. United States, 6267005. 2000-05-27
[56] Stayton S, Shimoboji T. Control of protein-ligand recognition using a stimuli-responsive polymer. Nature, 1995.378:472～474
[57] Steven P L. Cancer:has the smart bomb beendefused. Nature,1998.395:13～15
[58] 张阳德.纳米材料科学.北京:科技出版社,1994.113～135
[59] Kubo T, Sugita T, Shimose S. Targeted delivery of anticancer drugs with osteosarcoma-bearing hamsters, Int J Oncol,2000.17(2):309～315
[60] Muller H. Solid lipid nanoparticles(SLN) for controlled drug delivery. Eur J Pharm Biopharm,2000.50(1):161～177
[61] Ruan J M. Biocompatibility evaluation in vitro. Part Ⅰ:Morphology expression and proliferation of human and rat osteoblasts. J Central South University of Technology, 2001. 8(1): 1～8
[62] Nakada Y, Fattal E, Foulquier M, et al. Pharmacokunetics and biodistribution of oligonucleotide adsorbed onto poly isobutyl 1 cyanoarylate nanoparticle after intravenous administration in mice. Pbarm Res,1996.13(1):38
[63] Kossovsky N, Gelman A, Hnatyszyn HJ, et al. Surface-modified diamond nanoparticles as antigen delivery vehicles. Bioconjug Chem, 1995. 6:507～511
[64] 王兰.纳米在临床诊断及治疗研究中的进展.中国医师杂志,2002.4:225～226
[65] Bernard BK, Oscheroff MR, Hofman A, et al. Toxicology and carcinogenisis studies of dietary titanium dioxide-coated mica in male and female Fischer 344 rats. J Toxicol Environ Halth, 1989. 28:415～426
[66] Bischoff F, Bryson G. Tissue reaction to and fate of parenterally administered titanium dioxide. Res Commun Chem Pathol Pharmacol, 1982. 38:279～290
[67] 张士成,李世普,陈芳.磷灰石超微粉对癌细胞作用的初步研究.武汉工业大学学报,1996.18(1):5～8
[68] 张士成,李世普,袁润章.磷灰石超微粉对骨癌Os-732细胞形态的影响.武汉工业大学学报,1996.18(1):13～16
[69] 张士成,李世普,袁润章.磷灰石超微粉对胃癌MGc-803细胞集落形成和细胞骨架的影响.武汉工业大学学报,1996.18(1):9～11
[70] 张阳德.纳米生物技术用于恶性肿瘤治疗.科技日报,2001.11.02
[71] Okuda K. Hepatocellular carcinoma. J Hepatol,2000.32(suppl 1):225～237
[72] Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver Dis,1999.19:271～285
[73] El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med,1999.340:745～750
[74] Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol,2001.35:421～430
[75] Liaw YF, Tai DI, Chu CM, et al. Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis. A prospective study. Gastroenterology, 1986. 90:263～267
[76] Ng IOL, Lai ECS, Fan ST, et al. Prognostic significance of proliferating cell nuclear antigen expression in hepatocellular carcinoma. Cancer, 1994.73:2268
[77] Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer, 1985.56:918～928
[78] Bismuth H, Majno PE, Adam R. Liver transplantation for hepatocellular carcinoma. Semin Liver Dis, 1999.19:311～322
[79] Llovet JM, Bruix J, Gores GJ. Surgical resection versus transplantation for early hepatocellular carcinoma: clues for the best strategy. Hepatology,2000.31:1019～1021
[80] Nagasue N, Kohno H, Chang YC, et al. Liver resection for hepatocellular carcinoma. Results of 229 consecutive patients during 11 years. Ann Surg, 1993.217:375～384
[81] Sugioka A, Tsuzuki T, Kanai T. Postresection prognosis of patients with hepatocellular carcinoma. Surgery, 1993.113:612～618
[82] Iwatsuki S, Starzl TE. Role of liver tranplantation in the treatment of hepatocellular carcinoma. Semin Surg Oncol,1993.9:337
[83] Seaberg EC, Belle SH, Beringer KC, et al. Liver transplantation in the United States from 1987-1998: updated results from the Pitt-UNOS liver transplant registry. In: Cecka JM.Terasaki PI, eds. Clinical Transplants 1998. Los Angeles: UCLA Tissue Typing Laboratory, 1999.17-37
[84] LaBrecque DR. Neoplasia of the liver. ln:Kaplowitz N, ed. Liver and Biliary Diseases. Baltimore: Williams & Wilkins, 1996.391-436
[85] Holman M, Harrison D, Stewart A, et al. Neoadjuvant chemotherapy and orthotopic liver transplantation for hepatocellular carcinoma. N J Med, 1995.92:519-522
[86] Iwatsuki S, Starzl TE, Sheahan DG, et al. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg, 1991.214:221 -228
[87] Sarasin FP, Giostra E, Mentha G, et al. Partial hepatectomy or orthotopic liver transplantation for the treatment of resectable hepatocellular carcinoma? A cost-effectiveness perspective. Hepatology, 1998.28:436-442
[88] Colleoni M, Audisio RA, De Braud F, et al. Practical considerations in the treatment of hepatocellular carcinoma. Drugs,1998.55:367-382
[89] Lautt WW, Greenway CV. Conceptual review of the hepatic vascular bed. Hepatology, 1987.7:952-963
[90] Llovet JM, Sala M, Bruix J. Nonsurgical treatment of hepatocellular carcinoma. Liver Transpl,2000.6(6 suppl 2):S11-5
[91] Raoul JL, Heresbach D, Bretagne JF, et al. Chemoembolization of hepatocellular carcinomas. A study of the biodistribution and pharmacokinetics of doxorubicin. Cancer, 1992.70:585-590
[92] Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology,2002.35:1164-1171
[93] Trevisani F, De Notariis S, Rossi C, et al. Randomized control trials on chemoembolization for hepatocellular carcinoma: is there room for new studies? J din Gastroenterol,2001.32:383-389
[94] Venook AP, Stagg RJ, Lewis BJ, et al. Chemoembolization for hepatocellular carcinoma. J Clin Oncol,1990.8:l 108-1114
[95] Ernst O, Sergent G, Mizrahi D, et al. Treatment of hepatocellular carcinoma by trascatheter arterial chemoembolization: comparison of planned periodic chemoembolization and chemoembolization based on tumor response. A.IR Am J Roentgenol,1999.172:59-64
[96] Caturelli E, Siena DA, Fusilli S, et al. Transcalheter arterial chemoembolization for hepatocellular carcinoma in patients with cirrhosis: evaluation of damage to nontumorous liver tissue—long-term prospective study. Radiology,2000.215:123~128
[97] Di Carlo V, Ferrari G, Castoldi R, et al. Pre-operative chemoembolization of hepatocellular carcinoma in cirrhotic patients. Hepatogastroenterology, 1998.45:1950- 1954
[98] Roayaie S, Frischer JS, Emre SH, et al. Longterm results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann Surg,2002.235:533~539
[99] Takayasu K, Suzuki M, Uesaka K, et al. Hepatic artery embolization for inoperable hepatocellular carcinoma: prognosis and risk factors. Cancer Chemother Pharmacol, 1989.23(suppl):S123~S125
[100] Nerenstone SR, Ihde DC, Friedman MA. Clinical trials in primary hepatocellular carcinoma: current status and future directions. Cancer Treat Rev, 1988.15:1-31
[101] Kajanti M, Pyrhonen S, Mantyla M, et al. Intraarteria! and intravenous use of 4' epidoxorubicin combined with 5-fluorouracil in primary hepatocellular carcinoma. A randomized comparison. Am J Clin Oncol,1992.15:37~40
[102] Shiina S, Tagawa K, Unuma T, et al. Percutaneous ethanol injection therapy for hepatocellular carcinoma. A histopathologic study. Cancer,1991.68:1524~1530
[103] Livraghi T, Benedini V, Lazzaroni S, et al. Long term results of single session percutaneous ethanol injection in patients with large hepatocellular carcinoma. Cancer, 1998.83:48-57
[104] Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology, 1995.197:101-108
[105] D'Agostino HB, Solinas A. Percutaneous ablation therapy for hepatocellular carcinomas. AJR Am J Roentgenol, 1995.164:1165-1167
[106] Liang HL, Yang CF, Pan HB, et al. Small hepatocellular carcinoma: safety and efficacy of single high-dose percutaneous acetic acid injection for treatment. Radiology,2000.214:769-774
[107] Lin ZY, Wang JH, Hsieh MY, et al. Percutaneous ethanol injection of the supplying artery to hepatocellular carcinoma that is not amenable to conventional treatment. Br J Radiol,2000.73:833-839
[108] Curley SA, Izzo F, Ellis LM, et al. Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg,2000.232:381-391
[109] Cioni D, Lencioni R, Rossi S, et al. Radiofrequency thermal ablation of hepatocellular carcinoma: using contrast-enhanced harmonic power Doppler sonography to assess treatment outcome. AJR Am J Roentgenol,2001.177:783-788
[110] Rossi S, Di Stasi M, Buscarini E, et al. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR Am J Roentgenol,1996.167:759~768
[111] Wood TF, Rose DM, Chung M, et al. Radiofrequency ablation of 231 unresectable hepatic tumors: indications, limitations, and complications. Ann Surg Oncol,2000.7:593~600
[112] Horigotne H, Nomura T, Saso K, et al. Standards for selecting percutaneous ethanol
injection therapy or percutaneous microwave coagulation therapy for solitary small hepatocellular carcinoma: consideration of local recurrence. Am J Gastroenterol, 1999.94:1914-1917
[113] Itamoto T, Katayama K, Fukuda S, et al. Percutaneous microwave coagulation therapy for primary or recurrent hepatocellular carcinoma: long-term results. Hepatogastroenterology,2001.48:1401-1405
[114] Shibata T, Iimuro Y, Yamamoto Y, et al. Small hepatocellular carcinoma: comparison of radiofrequency ablation and percutaneous microwave coagulation therapy. Radiology,2002.223:331-337
[115] Ishida T, Murakami T, Shibata T, et al. Percutaneous microwave tumor coagulation for hepatocellular carcinomas with interruption of segmental hepatic blood flow. J Vasc Interv Radiol,2002.13:185~191
[116] Shibata T, Murakami T, Ogata N. Percutaneous microwave coagulation therapy for patients with primary and metastatic hepatic tumors during interruption of hepatic blood flow. Cancer,2000.88:302~311
[117] Seki T, Tamai T, Nakagawa T, et al. Combination therapy with transcatheter arterial chemoembolization and percutaneous microwave coagulation therapy for hepatocellular carcinoma. Cancer,2000.89:1245-1251
[118] Lezoche E, Paganini AM, Feliciotti F, et al. Ultrasound-guided laparoscopic cryoablation of hepatic tumors: preliminary report. World J Surg, 1998.22:829-835
[119] Seifert JK, Stewart GJ, Hewitt PM, et al. Interleukin-6 and tumor necrosis factor-alpha levels following hepatic cryotherapy: association with volume and duration of freezing. World J Surg,1999.23:1019~1026
[120] Matsuzaki Y, Osuga T, Saito Y, et al. A new, effective, and safe therapeutic option using proton irradiation for hepatocellular carcinoma. Gastroenterology.1994.106:1032
[121] Order S, Pajak T, Leibel S, et al. A randomized prospective trial comparing full dose chemotherapy to 1311 antiferritin: an RTOG study. Int J Radiat Oncol Biol Phys, 1991.20:953-963
[122] Raoul JL, Guyader D, Bretagne JF, et al Prospective randomized trial of chemoembolization versus intra-arterial injection of 1311-labeled-iodized oil in the treatment of hepatocellular carcinoma. Hepatology, 1997.26:1156-1161
[123] Itsubo M, Ishikawa T, Toda G, Tanaka M. Immunohistochemical study of expression and cellular localization of the multidrug resistance gene product p-glycoprotein in primary liver carcinoma. Cancer,1994.73:298
[124] Falkson G, Cnaan A, Simson 1W, et al. A randomized phase II study of acivicin and
4'deoxydoxorubicin in patients with hepatocellular carcinoma in an Eastern Cooperative Oncology Group study. Am J Clin Oncol,1990. 13:510～515
[125] Aguayo A, Patt YZ. Liver cancer. Clin Liver Dis,2001.5:479～507
[126] Manesis EK, Giannoulis G, Zoumboulis P, et al. Treatment of hepatocellular carcinoma with combined suppression and inhibition of sex hormones: a randomized, controlled trial. Hepatology, 1995.21:1535～1542
[127] Perrone F, Gallo C, Daniele B, et al. Tamoxifen in the treatment of hepatocellular carcinoma: 5-year results of the CLIP-1 multicentre randomized controlled trial. Curr Pharm Des,2002.8:1013～1019
[128] Liu CL, Fan ST, Ng IO, et al. Treatment of advanced hepatocellular carcinoma with tamoxifen and the correlation with expression of hormone receptors: a prospective randomized study. Am J Gastroenterol,2000.95:218～222
[129] Grimaldi C, Bleiberg H, Gay F, et al. Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma: results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial. J Clin Oncol, 1998.16:411～417
[130] Kouroumalis E, Skordilis P, Thermos K, et al. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut, 1998.42:442～447
[133] 陆东东.肝细胞癌免疫组化研究进展.诊断病理学杂志,1999.6(4)
[134] 叶胜龙.生物治疗在肝癌综合治疗中的应用.中国肿瘤生物治疗杂志,1999.6(3):174
[135] Ikeda K, Arase Y, Saitoh S, et al. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumo—a prospective randomized study of hepatitis C virus-related liver cancer. Hepatology,2000.32:228～232
[136] Lai CL, Lau JY, Wu PC, et al. Recombinant interferon-alpha in inoperable hepatocellular carcinoma: a randomized controlled trial. Hepatology, 1993.17:389～394
[137] Liovet JM, Sala M, Castells L, et al. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology,2000.31:54～58
[138] Kountouras J, Boura P, Karolides A, et al. Recombinant α2 interferon (α-IFN) with chemo-hormonal therapy in patients with hepatocellular carcinoma (HCC). Hepatogastroenterology, 1995.42:31～36
[139] Chung YH, Song IH, Song BC, et al. Combined therapy consisting of intraarterial cisplatin infusion and systemic interferon-alpha for hepatocellular carcinoma patients with major portal vein thrombosis or distant metastasis. Cancer,2000.88:1986～1991
[140] Hubert E.Blum.肝细胞癌的基因治疗.德国医学,2000.17(3):136～139
[141] Sangro B, Qian C, Schmitz V, et al. Gene therapy of hepatocellular carcinoma and gastrointestinal tumors. Ann N Y Acad Sci, 2002.963:6～12
[142] 汤钊猷,杨秉辉.原发性肝癌的研究与进展.上海:上海医科大学出版社,1990.302,43
[143] Chen RM. The establishment of a strain of human liver cell carcinoma in vitro and some preliminary observations. China Med J,1963.82:228
[144] Shen DW, Chen RM. Human hepatocellular carcinoma cells cultivated in vitro. In: Tang ZY, ed. Subclinical hepatocellular carcinoma. Berlin: Springer, 1985.336
[145] Tabor E. Tumor suppressor genes, growth factors, and oncogenes in hepatitis B virus-associated hepatocellular carcinoma. J Med Virol, 1994.42:357
[146] Livni N, Eid A, Ilan Y, et al. p53 expression in patients with cirrhosis with and without hepatocellular carcinoma. Cancer, 1995.75:2420
[147] Ng IOL, Lai ECS, Chan ASY, So MKP. Overexpression of p53 in hepatocellular carcinoma: a clinicopathological and prognostic correlation. J Gastroenterol Hepatol. 1995.10:250
[148] Inui Y, Hisgashiyama S, Kawata S, et al. Expression of heparin-binding epidermal growth factor in human gepatocellular carcinoma. Gastroenterology, 1994.107:1799
[149] Shirai Y, Kawata S, Tamura S, et al. Plasma transforming growth factor-β1 in patients with hepatocellular carcinoma-comparison with chromic liver disease. Cancer, 1994.73:2275
[150] Tanno S, Ogawa K. Abundant TGFα a precursor and EGF receptor expression as a possible mechanism for the preferential growth of carcinogen-induced prencoplastic and neoplastic hepatocytes in rats. Carcinogenesis, 1994.15: 1689
[151] Gu JR, Chen YQ, Hu LF. Studies on oncogenes in primary hepatie cancer and the status of HBV DNA. In: Tang ZY, Wu MC, Xia SS, eds. Primary living cancer. Berlin: Springer,1989.3
[152] 张士成,李世普,袁润章.磷灰石超微粉对胃癌MGc80-3细胞集落形成和细胞骨架的影响.武汉工业大学学报.1996.18(1):9～11
[153] 张士成,李世普,袁润章.磷灰石超微粉对骨癌Os-732细胞形态的影响.武汉工业大学学报,1996.18(1):12～15
[154] 冯凌云,阎玉华,陈闻杰,等.羟基磷灰石溶胶对W-256癌肉瘤细胞钙离子浓度及细胞形态结构的影响.中国生物医学工程学报,1999.17(4):374～377
[155] 夏清华,陈道达,林华,等.HASM对W-256细胞系DNA含量及细胞周期的影响.武汉工业大学学报,1999.21(2):5～6
[156] XIA Qinghua, NIE Haiyang, CHEN Daoda, et al. The Effect of Hydroxyapatite Ultrofine Powder on the Immunity Function of Tumor-bearing Mice. Journal of Tongji Medical University, 2001. 21 (2): 143～144,
[157] Prener J S. The growth and crystsallographic properties of calcium fluor-and chlorapatite crystals. Electrochem. Soc. Solid State Science, 1967. 114(1):77～83
[158] Roy D M, Eysel W, Dinger D. Hydrothermal synthesis of various carbonate containing calcium hydroxyapatite. Mater. Res. Bull.,1974.9:35～40
[159] Aoki H, Kato K, Shiba M. Synthesis of hydroxyapatite under hydrothermal conditions J. Dent. Apparatus and Materials,1972.13(27): 170～176
[160] Jarcho M, Bolen C H, Thomas M B. Hydroxylapatite synthesis and characterization in dense polycrystalline form. J. Mater. Sci.,1976.(1):2027～2035
[161] Legeros R Z. Apatites in Biological Systems. Prog. Crystal Growth Charact., 1981. 4:1～34
[162] Sim ionescu C I, Dum itriu S. Apatite:a new catalyst in synthetic organic chemistry. Chem Techol,1978.12:585～589
[163] Qiying M, Logan T J, Traina S J. Lead immobilization from aqueous solutions and contam inated soils using phosphate rocks. Environ Sci and Technol,1995.29:1118～1126
[164] Yuki I, Yokom izo Y. Inorganic phosphate materials. Sensa Gyntsn, 1981. 1: 23～27
[165] Shirkhanzadeh M. Direct formation of nanophase hydroxyapatite on cathodically polarized electrodes. Mater. Sci.:Mater. In Medicine, 1998.(9):727～729
[166] 薄颖慧,廖凯荣,卢泽俭等.聚乳酸/羟基磷灰石复合材料的研究Ⅰ.超细微羟基磷灰石的合成及表面处理.中山大学学报(自然科学版),1999.38(3):43～47
[167] 刘羽,钟康年,胡文云.溶胶凝胶法合成条件与羟基磷灰石特征的关系.材料科学与工程,1997.15(1):63～65
[168] 冯凌云,李世普,陈闻杰.羟基磷灰石溶胶对W 256癌肉瘤细胞和艾氏腹水瘤细胞增殖的影响.中国有色金属学报,1999.9(3):651～654
[169] Comodi P, Liu Y, Stoppa F, et al. A multimethod analysis of Si~-, S~- and REE~- rich apatite from a new find of kasilite bearing leucite(Abruzzi,ltaly). Mine Mag, 1999. 63(5):661～672
[170] Trueman N A. The structural of hydroxyapatite. Nature, 1996.1210:937～938
[171] 沈卫,顾燕芳,刘昌胜等.羟基磷灰石的表面特性.硅酸盐通报,1996.1:45～51
[172] 陈闻杰.羟基磷灰石溶胶稳定性研究及其抑癌机理初探:[硕士学位论文].武汉:武汉工业大学,1997
[173] 何毅,刘孝波,陈德娟等.纳米级β-磷酸钙的合成.合成化学.2000.8(2):96～99
[174] Hideki Aoki. Hedical Applications of Hydroxypapatite. Tokyo:Ishiyaku EuroAmerica Inc., 1994
[175] 王友法.羟基磷灰石晶须的合成及研究:[硕士学位论文].武汉:武汉理工大学,2001
[176] 冯凌云,陈芳,闫玉华.Sol-gol法制备HAP超微粉.武汉工业大学学报.1996,18(2):122～124
[177] 李革胜,李华基,彭晓东.冷冻干燥制备TiO_2超细粉体研究.重庆大学学报(自然科学 版),1999.22(1):95～98
[178] 刘继富,吴厚政,谈家琪等.冷冻干燥法制备MO-ZrO_2超细粉末.硅酸盐学报,1996.24(1):105～108
[179] 黄志良.溶胶—凝胶法合成羟基磷灰石的热稳定性研究.武汉化工学院学报,2002.24(2):
[180] 王欣宇,韩颖超.李世普.羟基磷灰石超微粉的柠檬酸盐法合成及表征.见:中国材料学会.2002年材料科学与工程新进展(下).北京:中国材料学会,2002.1467～1470
[181] 芮静安.肝癌治疗进展和展望.临床肝胆病杂志,2004.20(3):131～133
[182] 陈瑞铭,朱德厚,叶秀珍等.人体肝癌体外细胞系Bel-7402的建立及其特征.实验生物学报,1978.11(1):37
[183] 叶秀珍,朱德厚,沈鼎武.体外连续培养的肝细胞的超显微结构.实验生物学报.1980.13(4):362～365
[184] Mosmann T. Rapid colorimetic for cellular growth and survival:Application to proliferation and cytotoity assays. Immounol Methed, 1983.65:55
[185] 韩锐.抗癌药物研究与实验技术.北京:北京医科大学和中国协和医科大学联合出版社.1999.282～283,283～284,281～287
[186] 任玮玮.三氧化二砷对肝癌细胞株BEL-7402和SMMC-7721的作用及机制探讨:[硕士学位论文].广州:暨南大学,2003.14
[187] Chen RM. The establishment of a strain of human liver cell carcinoma in vitro and some preliminary observations. China Med J, 1963.82:228
[188] Bauscher, J. and W. I. Schaeffer. A diploid rat liver cell culture. I. Characterization and sensitivity to Aflatoxin B_1 In vitro, 1974.9:286～293
[189] Demoise C. F. et al. Tissue culture of adult human liver. Gastroenterology,1971.60:390～399
[190] 谭鲁鲁,周柔丽.医学细胞生物学.北京:北京医科大学和中国协和医科大学联合出版社,1992.198～204
[191] 罗琦.新型砷化物药敏性试验研究:[硕士学位论文].重庆:重庆大学,2003.18～25
[192] 唐胜利,袁媛,刘志苏等.羟基磷灰石纳米粒子对人肝癌BEL-7402细胞毒性的评价.肝脏,2003.8(1):21～24
[193] Zhi-Su Liu, Sheng-Li Tang, Zhing-Li Ai. Effects of hydroxyapatite nanoparticles on proliferation and apoptosis of human hepatoma BEL-7402 cells. World J Gastroenterol, 2003.9(9):1968～1971
[194] 应国华.电镜技术与细胞超微结构.香港:香港现代出版社,1993.31～50
[195] 韩颖超,李世普,曹献英等.冷冻干燥法制备纳米经基磷灰石粉体.见:中国材料学会. 纳米材料和技术应用进展——全国第三届纳米材料和技术应用会议论文集(上卷).南京:中国材料学会,2003.114～117
[196] 吴应荣,巢志瑜,潘巨祥.同步辐射微探针荧光分析.光谱实验室,1998.15(1):13～19
[197] 杜正通,黄东标,凌志强.顺铂诱导人骨肉瘤细胞凋亡及其分子机制的初步研究.中国误诊学杂志,2003.3(3):329～331
[198] Jens Meyer, Andreas F. Mack. Anthony W. Gummer. Pronounced infracuticular endocytosis in mammalian outer hair cells. Hearing Research, 2001. 161:10～22
[199] D. Dufrace, O. Cornu, C. Delloye, et al. Physical and chemical processing for a human dura mater substitute. Biomaterials, 2002.23:2979～2988
[200] Terasaki M. Labeling of the Endoplasmic Reticulum with DiO_6(3). Cell Biology: A Laboratory Handbook. Celis JE. Ed., 1998.501～506
[201] 戴维德,王雷,刘凡光等.应用激光扫描共聚焦显微成像术研究光敏剂亚细胞定位.中国激光医学杂志,2004.13(1):12～17
[202] Yuping Gong, Yanting Wang, Fanyuan Chen, et al. Identification of the subcellular localization of daunorubicin in multidrug-resistant K562 cell line. Leukemia Research, 2000.24:769～774
[203] 任卫.反相微乳液法制备纳米羟基磷灰石的研究:[博士学位论文].武汉:武汉理工大学,2003.70～88
[204] Tanaka H, Nuno Y, Irie S. Adsorption mechanism of poly-lysine on hydroxyapatite and its effect on dissolution properties of hydroxyapatite. Talanta,1992.39(8):893～898
[205] 吴应荣,巢志瑜等.怀孕期头发中一些元素含量的变化趋势.光谱学与光谱分析,1992.12(6):99～102
[206] Qian Q F, Feng W Y, et al. Study on the Effect of Supplementation of Iron-Fortied Food to Chinese Juvenile Athletes by Nuclear Analysis Technigues and Analysis J Radioanal. Nul. Chem. Letters, 1996.212(1):51～59
[207] 郑树,陈丽荣等.同步辐射对直肠癌组织微量元素测定的意义探讨.科技通报,1994.10(1):1～5
[208] 李楠.激光扫描共聚焦显微术.北京:人民军医出版社,1997.3～7
[209] 章静波.细胞生物学实用方法与技术.北京:北京医科大学和中国协和医科大学联合出版社,1995.
[210] 冯树,张福会,苏岩平等.培养的不同分化程度的人大肠癌细胞内质网结构特点.中国医科大学学报,2000.29(3):161～163
[211] Terasaki M., Song J, Wong J R, et al. Localization of endoplasmic reticulum on living and glutaraldehyde fixed cells with fluorescence dyes. Cell, 1984.38:101～108
[212] Toshihiko Tsutsumi, Akiro Tokumura, Shikifumi Kitazawa. Undifferentiated HL-6O cells internalize an antitumor alkyl ether phospholipid more rapidly than resistant K562 cells. Biochimica et Biophysica Acta, 1998.1390:73～84
[213] 汤钊猷,余业勤.原发性肝癌.上海:上海科学技术出版社,1999.362～371
[214] 蔡筱彦.凋亡素基因转入人类肝癌细胞诱导细胞凋亡研究:[硕士学位论文].广州:暨南大学,2002.11
[215] 谢冰芬,冯公侃,朱孝峰等.茶多酚对人癌细胞和人体细胞增殖及凋亡的实验研究.中草药,2003.6:540～543
[216] CAO Xian-ying, LI Shi-pu, ZHANG Ran, et al. Effect on the Hepatocellular Carcinoma Cell Proliferation and Cell Cycle Treated with Hydroxyapatite Nanoparticles. CttINA J CANCER PREV TREAT, 2003. 10(3):256～258
[217] 许迅辉,王国民,任豫申.应用吖啶橙染色法检查尿液癌细胞的评价.国外医学临床生物化学与检验学分册,2001.22(4):220
[218] George P, Han J, Watnab T, et al. Quantitative fluorescence measurements of AO stained normal and malignant bladder cells, Int J Cancer, 1983. 31:577
[219] 张覃沐.抗肿瘤药物的药理与临床应用.郑州:河南医科大学出版社,1999.10～14
[220] Shao JC, Wu JF, Wang DB, et al. Relationship between the expression of human telomerase reverse transcriptase gene and cell cycle regulators in gastric cancer and its significance. World J Gastroenterol, 2003.9(3):427～431
[221] 吴波,周晓军.细胞凋亡的检测方法.临床与实验病理学杂志.1997.13(3):262～263
[222] 云径平,林汉良,吴秋良.食管小细胞癌的临床病理、免疫组化及电镜观察.癌症,1998.17(4):251～253
[223] 胡军祥,虞研原,葛云法.肿瘤细胞深低温冷冻后的功能和超微结构变化的研究.科技通报,1995.11(6):341～346
[224] 魏文,冯宇霞,张双喜等.吖啶橙与碘化丙啶检测细胞DNA方法的比较.中华物理医学杂志,1994.16(3):166～169
[225] Ying Wang, Xianting Li, Lu Wang, et al. An alternative form of paraptosis-like cell death, triggered by TAJ/TROY and enhanced by PDCD5 overexpression. Journal of Cell Science, 117(8): 1525～1532
[226] Asher E, Payne CM, Bernstein C. Evaluation of cell death in EBV-transfonned lymphocytes using agarose gel electrophresis,light microscopy and electron microscopy. Ⅱ Induction of non-classic apoptosis(para-apoptosis) by tritiaied thymidine. leuk lymphoma, 1995.19(1-2):107～119
[227] Kitanaka C, Kuchino Y. Caspase independent programmed cell death with necrotic orphology. Cell Death Differ, 1999.6(6):508～515
[228] Lorenzen J, thiele J, Fischer R. The mummified Hodgkin: cell death in Hodgkin's eisease. J Pathol, 1997.182:288～298
[229] Sabina Sperandio, Ian de Belle, Dale E. Bredesen. An alternative, nonapoptotic form of programmed cell death. Cell Biology,2000. 97(26): 14376～14381
[230] Forcet C, Ye X, Granger L, et al. The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation. PNA S,2001.98(6):3416～3421
[231] Jacobson M D, Weil M, Raff M C. Programmed cell death in animal development. Cell, 1997.88(3):347～35
[232] 孙靖中,邹雄.肿瘤分子生物学.北京:人民卫生出版社,1998.142～144
[233] HeTc, SparksAb, Ragoc, et al. Indentic c-myc as a targetgene of APC. Science, 1998, 282:1499～1513
[234] Skouteris GG, Schroder CH. C-myc is required for the G_0/G_1-stransition of primary hepatocytes stimulated with a deleted form of hepatocytes growth factor. Biochem,1996.316:879～886
[235] Caelles C, Heimberg A, Karin M. A new function for p53 in poptosis. Trends Cell Biol, 1994.4:356-364
[2] 薛群基,徐康.纳米化学.化学进展,2000.12(4):431～444
[3] 张志昆,崔作林.纳米技术与纳米材料.北京:国防工业出版社,2000.10
[4] 解思深,张立德.创新者的报告之纳米科学与技术研究成果专著.北京:科学出版社,2000.12
[5] 王宏飞.美国启动《癌症纳米技术计划》.全球科技经济瞭望,2004.12:4～5
[6] 中国康凯信息咨询公司.中国纳米技术行业研究报告.2005.3
[7] Clark LC, Ddalkin B, Krongrad A, et al. Decreased incidence of prostate cancer with selenium supplementation: results of a double-bilnd cancer prevention trial. Br J Urol,1998.81 (5):730～4
[8] Patterson BH, Levander OA. Naturally occurring selenium compounds in cancer chemoprevention trials:a workshop summary. Cancer Epidemiol Biomarkers Prey, 1997.6(1):63～9
[9] Combs GF Jr, Clark LC, Turnbull B W. Reduction of cancer mortality and incidence by selenium supplementation. Med Klin,1997.92(Suppl 3):42～45
[10] Bronzetti G, della Croce C. Selenium: its important roles in life and contrasting aspects. J Environ Patho Toxicol Oncol,1993.12(2):59～71
[11] Gao Xueyun, Zhang Jinsong, Zhang Lide. Hollow sphere selenium nanoparticles: their In-Vitro Anti Hydroxyl Radical Effect. Adv Mater,2002.14(4):290～293
[12] 朱茂祥,张松,杨陟华,等.纳米硒对 4-甲基硝胺-1-(3-吡啶)-1-丁酮诱发昆明小鼠肺癌的防治研究.癌症,2000.19(10):883
[13] Yi DK, Kim DY. Polymer nanosphere lithography: fabrication of an ordered trigonal polymeric nanostructure. Chem Commun (Camb),2003.21:982～983
[14] Labhasetwar V, Song C. Nanoparticle drug delivery system for restenosis. Advanced Drug alivery Reviews, 1997.24:63～86
[15] Allcock H R, Pucker S R. Poly((amino acid ester) phosphazenes) as substrates for the controlled release of small molecules. Biomaterials, 1994.15:563
[16] Fu K, Griebenow K, Hsieh L, et al. FT-IR characterization of the secondary structure of proteins encapsulated within PLGA microspheres. J Controlled Release, 1999.58:357～369
[17] Taylor J R, Fang M M, Nie S M A. Probing specific sequences in single DNA molecule with bioconjugated fluorescent nanoparticles. Chemistry,2000. 72(9):1979～1986
[18] Cleland L, Jobnson J. Recombinant human growth hormonepoly(lactic-co-glycolic acid) microsphere formulation development. Advanced Drug Delivery Reviews, 1998.28:71～84
[19] Mattson M P, Haddon R C, Rao A M. Molecular functionalization of carbon nanotubes and use as substrates for neuronal growth. J Mol Nurosci,2000.14:175～82
[20] Haynes C L, Van Dayne R P. Nanosphere lithograpby. J Plays Chem(B),2001.105:5599～5611
[21] Chen X Y, Li J R. Thromboxane A2 regulation of endothelial cell migration, angiogenesis, and tumor matestasis. Biochem & Biophys Res Commun, 1998.245:352
[22] Storhoff J J, Elghanian R, Mucic R C J. One-pot colorimetric differentiation of polynucleotides with single base imperfections using gold nanoparticle pbobles. Am Chem Soc, 1998. 120:195
[23] Lin L, Zhao H Q. Receptor activity. Biochem & Biophys Res Commun,2000.274:817
[24] Bruchez J. Semiconduct nanocrystals as fluorescent biological labels. Science, 1998.281:2031～2033
[25] Lacoste E. Super-resolution molecular ruler using single quantum dots. J Biophysics,2000.78:402A
[26] 贺达仁,谢嘉平.影响21世纪医学进程的纳米技术.医学与哲学,2000.21(2):31～32
[27] Silva GA. Introduction to nanotechnology and its applicalions to medicine. Surg Neurol,2004.61:216～220
[28] Lewin M, Carlesso N, Tung CH, et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat Biotechnol,2000.18:410～414
[29] 秦仁义,裘法祖.纳米生物技术在实验外科的应用前景.中华实验外科杂志,2003.20:773～775
[30] Tiefenauer LX, Tschirky A, KKne G, et al.. Invivo evaluation of magnetite nanoparticles for use as a tumor contrast agent in MRI. Magn Reson Imaging,1996.14(4):391～394
[31] 陈丽英.中国率先应用纳米技术诊断肝癌.中国新药杂志,2004.13(6):564
[32] Jordan A. Nanotechnology and consequences for surgical oncology. Kongressbd Dtsch Ges Chir Kongr,2002.119:821～828
[33] Majeti V J. Nano and microparticles as controlled drug delivery devices. Pharm Pharmaceut Sci, 2000.3:234～258
[34] Labhasetwar V, Chen B, Muller M. Gene-based therapies for restenosis and others source. Advanced Drug Delivery Reviews, 1997. 24: 109～122
[35] Griffith L. Polymer biomaterials. Materialia, 2000. 48:263～277
[36] Peppas A. Drug diffusion and binding in ionizable interpenetrating networks from poly(vinyl alcohol) and poly(acrylic acid). Eru J Pharm Biopharm, 1998. 46(1):15～30
[37] Cleland L. Solvent evaporation processes for the production of controlled release biodegradable microsphere formulations for therapeutics and vaccines. Biotechnology Progress, 1998.14:102-107
[38] Rajaram C. Electrochemical and spectroscopic characterization of self-assembled monolayers of ferrocenylalkyl compounds with amide linkages. J Surfaces and Colloids,1998.14:124~136
[39] Dubois J C, Exbrayat P, Couble M L, et al. Effect of new machinable ceramic on behavior of rat bone cells cultured in vitro. J Biomed Mater Res, 1998.43:215-225
[40] Hanes J, Cleland L. New advances in microsphere-based single-dose vaccines. Advanced Drug Delivery Reviews,1998.28:97~120
[41] Garrett Q, Chatelier C. Effect of charged groups on the adsorption and penetration of proteins onto and into carboxymethylated poly(HEMA)hydrogels. Biomaterials, 1998.19:2175-2183
[42] Black J. Biological performance of materials:fundamentals of biocompatibility. New York:Marcell Dekker Inc, 1992.25-109
[43] Kwon S. Polymeric micelles as new drug carriers. Advanced Drug Delivery Reviews,1996.21:107~125
[44] Dunn E, Coombes A G A. In vitro cell interaction and in vivo biodistribution of poly( lactide-co-glycolide) nanospheres surface modified by poloxamer and poloxamine copolymers. J Controlled Release, 1997.44:65-71
[45] Langer R. Drug delivery and targeting- The design of degradable materials and the development of intelligent delivery systems have had an enormous impact on drug-based therapies. Nature, 1998.392:5-9
[46] Na K, Park KH, Kim SW, et al. Self-assembled hydrogel nanoparticles from curdlan derivatives: characterization, anti-cancer drug release and interaction with a hepatoma cell (HepG2). J Controlled Release,2000.699:225~236
[47] Na K, Bum Lee T, Park KH, et al. Self-assembled nanoparticles of hydrophobically modified polysaccharide bearing vitamin H as a targeted anti-cancer drug delivery system. Eur J Pharm Sci,2003.18(2): 165-173
[48] Mao HQ, Roy K, Troung-Le VL, et al. Chitosan-DNA nanoparticles as gene carriers: synthesis, characterization and transfection efficiency. J Control Releasc,2001.70:399-421
[49] Ito A, Matsuoka F, Honda H, et al. Antitumor effects of combined therapy of recombinant heat shock protein 70 and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma. Cancer Immunol Immunother,2004.53:26~32
[50] Eichman JD, Bielinska AU, Kukowska-Latallo JF, et al. The use of PAMAM dendrimers in
the efficient transfer of genetic material into cells. Pharm Sci Technol Today,2000.3:232～245
[51] Reynolds AR, Moein Moghimi S, Hodivala-Dilke K. Nanoparticle-mediated gene delivery to tumour neovaseulature. Trends Mol Med,2003.9:2～4
[52] KRISHNA R, MAYER LD. Multidrug resistance(MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci,2000. 11(4):265～283
[53] SOMA CE, DUBERNET C, BENTOLILA D, et al. Reversion of multidrug resistance by co-encapsulation of doxorubicin and cyclosporin A in polyalkylcyanoacrylate nanoparticles. Bio materials,2000.21 (1): 1～7
[54] Vandorpe J, Schacht E. Poly(organo phosphazene) nanoparticles surface modified with poly(ethylene oxide). Biotechnology and Bioengineering, 1996.52:89～95
[55] Samsavar L. Dual stage instrument for scanning a specimen. United States, 6267005. 2000-05-27
[56] Stayton S, Shimoboji T. Control of protein-ligand recognition using a stimuli-responsive polymer. Nature, 1995.378:472～474
[57] Steven P L. Cancer:has the smart bomb beendefused. Nature,1998.395:13～15
[58] 张阳德.纳米材料科学.北京:科技出版社,1994.113～135
[59] Kubo T, Sugita T, Shimose S. Targeted delivery of anticancer drugs with osteosarcoma-bearing hamsters, Int J Oncol,2000.17(2):309～315
[60] Muller H. Solid lipid nanoparticles(SLN) for controlled drug delivery. Eur J Pharm Biopharm,2000.50(1):161～177
[61] Ruan J M. Biocompatibility evaluation in vitro. Part Ⅰ:Morphology expression and proliferation of human and rat osteoblasts. J Central South University of Technology, 2001. 8(1): 1～8
[62] Nakada Y, Fattal E, Foulquier M, et al. Pharmacokunetics and biodistribution of oligonucleotide adsorbed onto poly isobutyl 1 cyanoarylate nanoparticle after intravenous administration in mice. Pbarm Res,1996.13(1):38
[63] Kossovsky N, Gelman A, Hnatyszyn HJ, et al. Surface-modified diamond nanoparticles as antigen delivery vehicles. Bioconjug Chem, 1995. 6:507～511
[64] 王兰.纳米在临床诊断及治疗研究中的进展.中国医师杂志,2002.4:225～226
[65] Bernard BK, Oscheroff MR, Hofman A, et al. Toxicology and carcinogenisis studies of dietary titanium dioxide-coated mica in male and female Fischer 344 rats. J Toxicol Environ Halth, 1989. 28:415～426
[66] Bischoff F, Bryson G. Tissue reaction to and fate of parenterally administered titanium dioxide. Res Commun Chem Pathol Pharmacol, 1982. 38:279～290
[67] 张士成,李世普,陈芳.磷灰石超微粉对癌细胞作用的初步研究.武汉工业大学学报,1996.18(1):5～8
[68] 张士成,李世普,袁润章.磷灰石超微粉对骨癌Os-732细胞形态的影响.武汉工业大学学报,1996.18(1):13～16
[69] 张士成,李世普,袁润章.磷灰石超微粉对胃癌MGc-803细胞集落形成和细胞骨架的影响.武汉工业大学学报,1996.18(1):9～11
[70] 张阳德.纳米生物技术用于恶性肿瘤治疗.科技日报,2001.11.02
[71] Okuda K. Hepatocellular carcinoma. J Hepatol,2000.32(suppl 1):225～237
[72] Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver Dis,1999.19:271～285
[73] El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med,1999.340:745～750
[74] Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol,2001.35:421～430
[75] Liaw YF, Tai DI, Chu CM, et al. Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis. A prospective study. Gastroenterology, 1986. 90:263～267
[76] Ng IOL, Lai ECS, Fan ST, et al. Prognostic significance of proliferating cell nuclear antigen expression in hepatocellular carcinoma. Cancer, 1994.73:2268
[77] Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer, 1985.56:918～928
[78] Bismuth H, Majno PE, Adam R. Liver transplantation for hepatocellular carcinoma. Semin Liver Dis, 1999.19:311～322
[79] Llovet JM, Bruix J, Gores GJ. Surgical resection versus transplantation for early hepatocellular carcinoma: clues for the best strategy. Hepatology,2000.31:1019～1021
[80] Nagasue N, Kohno H, Chang YC, et al. Liver resection for hepatocellular carcinoma. Results of 229 consecutive patients during 11 years. Ann Surg, 1993.217:375～384
[81] Sugioka A, Tsuzuki T, Kanai T. Postresection prognosis of patients with hepatocellular carcinoma. Surgery, 1993.113:612～618
[82] Iwatsuki S, Starzl TE. Role of liver tranplantation in the treatment of hepatocellular carcinoma. Semin Surg Oncol,1993.9:337
[83] Seaberg EC, Belle SH, Beringer KC, et al. Liver transplantation in the United States from 1987-1998: updated results from the Pitt-UNOS liver transplant registry. In: Cecka JM.Terasaki PI, eds. Clinical Transplants 1998. Los Angeles: UCLA Tissue Typing Laboratory, 1999.17-37
[84] LaBrecque DR. Neoplasia of the liver. ln:Kaplowitz N, ed. Liver and Biliary Diseases. Baltimore: Williams & Wilkins, 1996.391-436
[85] Holman M, Harrison D, Stewart A, et al. Neoadjuvant chemotherapy and orthotopic liver transplantation for hepatocellular carcinoma. N J Med, 1995.92:519-522
[86] Iwatsuki S, Starzl TE, Sheahan DG, et al. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg, 1991.214:221 -228
[87] Sarasin FP, Giostra E, Mentha G, et al. Partial hepatectomy or orthotopic liver transplantation for the treatment of resectable hepatocellular carcinoma? A cost-effectiveness perspective. Hepatology, 1998.28:436-442
[88] Colleoni M, Audisio RA, De Braud F, et al. Practical considerations in the treatment of hepatocellular carcinoma. Drugs,1998.55:367-382
[89] Lautt WW, Greenway CV. Conceptual review of the hepatic vascular bed. Hepatology, 1987.7:952-963
[90] Llovet JM, Sala M, Bruix J. Nonsurgical treatment of hepatocellular carcinoma. Liver Transpl,2000.6(6 suppl 2):S11-5
[91] Raoul JL, Heresbach D, Bretagne JF, et al. Chemoembolization of hepatocellular carcinomas. A study of the biodistribution and pharmacokinetics of doxorubicin. Cancer, 1992.70:585-590
[92] Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology,2002.35:1164-1171
[93] Trevisani F, De Notariis S, Rossi C, et al. Randomized control trials on chemoembolization for hepatocellular carcinoma: is there room for new studies? J din Gastroenterol,2001.32:383-389
[94] Venook AP, Stagg RJ, Lewis BJ, et al. Chemoembolization for hepatocellular carcinoma. J Clin Oncol,1990.8:l 108-1114
[95] Ernst O, Sergent G, Mizrahi D, et al. Treatment of hepatocellular carcinoma by trascatheter arterial chemoembolization: comparison of planned periodic chemoembolization and chemoembolization based on tumor response. A.IR Am J Roentgenol,1999.172:59-64
[96] Caturelli E, Siena DA, Fusilli S, et al. Transcalheter arterial chemoembolization for hepatocellular carcinoma in patients with cirrhosis: evaluation of damage to nontumorous liver tissue—long-term prospective study. Radiology,2000.215:123~128
[97] Di Carlo V, Ferrari G, Castoldi R, et al. Pre-operative chemoembolization of hepatocellular carcinoma in cirrhotic patients. Hepatogastroenterology, 1998.45:1950- 1954
[98] Roayaie S, Frischer JS, Emre SH, et al. Longterm results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann Surg,2002.235:533~539
[99] Takayasu K, Suzuki M, Uesaka K, et al. Hepatic artery embolization for inoperable hepatocellular carcinoma: prognosis and risk factors. Cancer Chemother Pharmacol, 1989.23(suppl):S123~S125
[100] Nerenstone SR, Ihde DC, Friedman MA. Clinical trials in primary hepatocellular carcinoma: current status and future directions. Cancer Treat Rev, 1988.15:1-31
[101] Kajanti M, Pyrhonen S, Mantyla M, et al. Intraarteria! and intravenous use of 4' epidoxorubicin combined with 5-fluorouracil in primary hepatocellular carcinoma. A randomized comparison. Am J Clin Oncol,1992.15:37~40
[102] Shiina S, Tagawa K, Unuma T, et al. Percutaneous ethanol injection therapy for hepatocellular carcinoma. A histopathologic study. Cancer,1991.68:1524~1530
[103] Livraghi T, Benedini V, Lazzaroni S, et al. Long term results of single session percutaneous ethanol injection in patients with large hepatocellular carcinoma. Cancer, 1998.83:48-57
[104] Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology, 1995.197:101-108
[105] D'Agostino HB, Solinas A. Percutaneous ablation therapy for hepatocellular carcinomas. AJR Am J Roentgenol, 1995.164:1165-1167
[106] Liang HL, Yang CF, Pan HB, et al. Small hepatocellular carcinoma: safety and efficacy of single high-dose percutaneous acetic acid injection for treatment. Radiology,2000.214:769-774
[107] Lin ZY, Wang JH, Hsieh MY, et al. Percutaneous ethanol injection of the supplying artery to hepatocellular carcinoma that is not amenable to conventional treatment. Br J Radiol,2000.73:833-839
[108] Curley SA, Izzo F, Ellis LM, et al. Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg,2000.232:381-391
[109] Cioni D, Lencioni R, Rossi S, et al. Radiofrequency thermal ablation of hepatocellular carcinoma: using contrast-enhanced harmonic power Doppler sonography to assess treatment outcome. AJR Am J Roentgenol,2001.177:783-788
[110] Rossi S, Di Stasi M, Buscarini E, et al. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR Am J Roentgenol,1996.167:759~768
[111] Wood TF, Rose DM, Chung M, et al. Radiofrequency ablation of 231 unresectable hepatic tumors: indications, limitations, and complications. Ann Surg Oncol,2000.7:593~600
[112] Horigotne H, Nomura T, Saso K, et al. Standards for selecting percutaneous ethanol
injection therapy or percutaneous microwave coagulation therapy for solitary small hepatocellular carcinoma: consideration of local recurrence. Am J Gastroenterol, 1999.94:1914-1917
[113] Itamoto T, Katayama K, Fukuda S, et al. Percutaneous microwave coagulation therapy for primary or recurrent hepatocellular carcinoma: long-term results. Hepatogastroenterology,2001.48:1401-1405
[114] Shibata T, Iimuro Y, Yamamoto Y, et al. Small hepatocellular carcinoma: comparison of radiofrequency ablation and percutaneous microwave coagulation therapy. Radiology,2002.223:331-337
[115] Ishida T, Murakami T, Shibata T, et al. Percutaneous microwave tumor coagulation for hepatocellular carcinomas with interruption of segmental hepatic blood flow. J Vasc Interv Radiol,2002.13:185~191
[116] Shibata T, Murakami T, Ogata N. Percutaneous microwave coagulation therapy for patients with primary and metastatic hepatic tumors during interruption of hepatic blood flow. Cancer,2000.88:302~311
[117] Seki T, Tamai T, Nakagawa T, et al. Combination therapy with transcatheter arterial chemoembolization and percutaneous microwave coagulation therapy for hepatocellular carcinoma. Cancer,2000.89:1245-1251
[118] Lezoche E, Paganini AM, Feliciotti F, et al. Ultrasound-guided laparoscopic cryoablation of hepatic tumors: preliminary report. World J Surg, 1998.22:829-835
[119] Seifert JK, Stewart GJ, Hewitt PM, et al. Interleukin-6 and tumor necrosis factor-alpha levels following hepatic cryotherapy: association with volume and duration of freezing. World J Surg,1999.23:1019~1026
[120] Matsuzaki Y, Osuga T, Saito Y, et al. A new, effective, and safe therapeutic option using proton irradiation for hepatocellular carcinoma. Gastroenterology.1994.106:1032
[121] Order S, Pajak T, Leibel S, et al. A randomized prospective trial comparing full dose chemotherapy to 1311 antiferritin: an RTOG study. Int J Radiat Oncol Biol Phys, 1991.20:953-963
[122] Raoul JL, Guyader D, Bretagne JF, et al Prospective randomized trial of chemoembolization versus intra-arterial injection of 1311-labeled-iodized oil in the treatment of hepatocellular carcinoma. Hepatology, 1997.26:1156-1161
[123] Itsubo M, Ishikawa T, Toda G, Tanaka M. Immunohistochemical study of expression and cellular localization of the multidrug resistance gene product p-glycoprotein in primary liver carcinoma. Cancer,1994.73:298
[124] Falkson G, Cnaan A, Simson 1W, et al. A randomized phase II study of acivicin and
4'deoxydoxorubicin in patients with hepatocellular carcinoma in an Eastern Cooperative Oncology Group study. Am J Clin Oncol,1990. 13:510～515
[125] Aguayo A, Patt YZ. Liver cancer. Clin Liver Dis,2001.5:479～507
[126] Manesis EK, Giannoulis G, Zoumboulis P, et al. Treatment of hepatocellular carcinoma with combined suppression and inhibition of sex hormones: a randomized, controlled trial. Hepatology, 1995.21:1535～1542
[127] Perrone F, Gallo C, Daniele B, et al. Tamoxifen in the treatment of hepatocellular carcinoma: 5-year results of the CLIP-1 multicentre randomized controlled trial. Curr Pharm Des,2002.8:1013～1019
[128] Liu CL, Fan ST, Ng IO, et al. Treatment of advanced hepatocellular carcinoma with tamoxifen and the correlation with expression of hormone receptors: a prospective randomized study. Am J Gastroenterol,2000.95:218～222
[129] Grimaldi C, Bleiberg H, Gay F, et al. Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma: results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial. J Clin Oncol, 1998.16:411～417
[130] Kouroumalis E, Skordilis P, Thermos K, et al. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut, 1998.42:442～447
[133] 陆东东.肝细胞癌免疫组化研究进展.诊断病理学杂志,1999.6(4)
[134] 叶胜龙.生物治疗在肝癌综合治疗中的应用.中国肿瘤生物治疗杂志,1999.6(3):174
[135] Ikeda K, Arase Y, Saitoh S, et al. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumo—a prospective randomized study of hepatitis C virus-related liver cancer. Hepatology,2000.32:228～232
[136] Lai CL, Lau JY, Wu PC, et al. Recombinant interferon-alpha in inoperable hepatocellular carcinoma: a randomized controlled trial. Hepatology, 1993.17:389～394
[137] Liovet JM, Sala M, Castells L, et al. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology,2000.31:54～58
[138] Kountouras J, Boura P, Karolides A, et al. Recombinant α2 interferon (α-IFN) with chemo-hormonal therapy in patients with hepatocellular carcinoma (HCC). Hepatogastroenterology, 1995.42:31～36
[139] Chung YH, Song IH, Song BC, et al. Combined therapy consisting of intraarterial cisplatin infusion and systemic interferon-alpha for hepatocellular carcinoma patients with major portal vein thrombosis or distant metastasis. Cancer,2000.88:1986～1991
[140] Hubert E.Blum.肝细胞癌的基因治疗.德国医学,2000.17(3):136～139
[141] Sangro B, Qian C, Schmitz V, et al. Gene therapy of hepatocellular carcinoma and gastrointestinal tumors. Ann N Y Acad Sci, 2002.963:6～12
[142] 汤钊猷,杨秉辉.原发性肝癌的研究与进展.上海:上海医科大学出版社,1990.302,43
[143] Chen RM. The establishment of a strain of human liver cell carcinoma in vitro and some preliminary observations. China Med J,1963.82:228
[144] Shen DW, Chen RM. Human hepatocellular carcinoma cells cultivated in vitro. In: Tang ZY, ed. Subclinical hepatocellular carcinoma. Berlin: Springer, 1985.336
[145] Tabor E. Tumor suppressor genes, growth factors, and oncogenes in hepatitis B virus-associated hepatocellular carcinoma. J Med Virol, 1994.42:357
[146] Livni N, Eid A, Ilan Y, et al. p53 expression in patients with cirrhosis with and without hepatocellular carcinoma. Cancer, 1995.75:2420
[147] Ng IOL, Lai ECS, Chan ASY, So MKP. Overexpression of p53 in hepatocellular carcinoma: a clinicopathological and prognostic correlation. J Gastroenterol Hepatol. 1995.10:250
[148] Inui Y, Hisgashiyama S, Kawata S, et al. Expression of heparin-binding epidermal growth factor in human gepatocellular carcinoma. Gastroenterology, 1994.107:1799
[149] Shirai Y, Kawata S, Tamura S, et al. Plasma transforming growth factor-β1 in patients with hepatocellular carcinoma-comparison with chromic liver disease. Cancer, 1994.73:2275
[150] Tanno S, Ogawa K. Abundant TGFα a precursor and EGF receptor expression as a possible mechanism for the preferential growth of carcinogen-induced prencoplastic and neoplastic hepatocytes in rats. Carcinogenesis, 1994.15: 1689
[151] Gu JR, Chen YQ, Hu LF. Studies on oncogenes in primary hepatie cancer and the status of HBV DNA. In: Tang ZY, Wu MC, Xia SS, eds. Primary living cancer. Berlin: Springer,1989.3
[152] 张士成,李世普,袁润章.磷灰石超微粉对胃癌MGc80-3细胞集落形成和细胞骨架的影响.武汉工业大学学报.1996.18(1):9～11
[153] 张士成,李世普,袁润章.磷灰石超微粉对骨癌Os-732细胞形态的影响.武汉工业大学学报,1996.18(1):12～15
[154] 冯凌云,阎玉华,陈闻杰,等.羟基磷灰石溶胶对W-256癌肉瘤细胞钙离子浓度及细胞形态结构的影响.中国生物医学工程学报,1999.17(4):374～377
[155] 夏清华,陈道达,林华,等.HASM对W-256细胞系DNA含量及细胞周期的影响.武汉工业大学学报,1999.21(2):5～6
[156] XIA Qinghua, NIE Haiyang, CHEN Daoda, et al. The Effect of Hydroxyapatite Ultrofine Powder on the Immunity Function of Tumor-bearing Mice. Journal of Tongji Medical University, 2001. 21 (2): 143～144,
[157] Prener J S. The growth and crystsallographic properties of calcium fluor-and chlorapatite crystals. Electrochem. Soc. Solid State Science, 1967. 114(1):77～83
[158] Roy D M, Eysel W, Dinger D. Hydrothermal synthesis of various carbonate containing calcium hydroxyapatite. Mater. Res. Bull.,1974.9:35～40
[159] Aoki H, Kato K, Shiba M. Synthesis of hydroxyapatite under hydrothermal conditions J. Dent. Apparatus and Materials,1972.13(27): 170～176
[160] Jarcho M, Bolen C H, Thomas M B. Hydroxylapatite synthesis and characterization in dense polycrystalline form. J. Mater. Sci.,1976.(1):2027～2035
[161] Legeros R Z. Apatites in Biological Systems. Prog. Crystal Growth Charact., 1981. 4:1～34
[162] Sim ionescu C I, Dum itriu S. Apatite:a new catalyst in synthetic organic chemistry. Chem Techol,1978.12:585～589
[163] Qiying M, Logan T J, Traina S J. Lead immobilization from aqueous solutions and contam inated soils using phosphate rocks. Environ Sci and Technol,1995.29:1118～1126
[164] Yuki I, Yokom izo Y. Inorganic phosphate materials. Sensa Gyntsn, 1981. 1: 23～27
[165] Shirkhanzadeh M. Direct formation of nanophase hydroxyapatite on cathodically polarized electrodes. Mater. Sci.:Mater. In Medicine, 1998.(9):727～729
[166] 薄颖慧,廖凯荣,卢泽俭等.聚乳酸/羟基磷灰石复合材料的研究Ⅰ.超细微羟基磷灰石的合成及表面处理.中山大学学报(自然科学版),1999.38(3):43～47
[167] 刘羽,钟康年,胡文云.溶胶凝胶法合成条件与羟基磷灰石特征的关系.材料科学与工程,1997.15(1):63～65
[168] 冯凌云,李世普,陈闻杰.羟基磷灰石溶胶对W 256癌肉瘤细胞和艾氏腹水瘤细胞增殖的影响.中国有色金属学报,1999.9(3):651～654
[169] Comodi P, Liu Y, Stoppa F, et al. A multimethod analysis of Si~-, S~- and REE~- rich apatite from a new find of kasilite bearing leucite(Abruzzi,ltaly). Mine Mag, 1999. 63(5):661～672
[170] Trueman N A. The structural of hydroxyapatite. Nature, 1996.1210:937～938
[171] 沈卫,顾燕芳,刘昌胜等.羟基磷灰石的表面特性.硅酸盐通报,1996.1:45～51
[172] 陈闻杰.羟基磷灰石溶胶稳定性研究及其抑癌机理初探:[硕士学位论文].武汉:武汉工业大学,1997
[173] 何毅,刘孝波,陈德娟等.纳米级β-磷酸钙的合成.合成化学.2000.8(2):96～99
[174] Hideki Aoki. Hedical Applications of Hydroxypapatite. Tokyo:Ishiyaku EuroAmerica Inc., 1994
[175] 王友法.羟基磷灰石晶须的合成及研究:[硕士学位论文].武汉:武汉理工大学,2001
[176] 冯凌云,陈芳,闫玉华.Sol-gol法制备HAP超微粉.武汉工业大学学报.1996,18(2):122～124
[177] 李革胜,李华基,彭晓东.冷冻干燥制备TiO_2超细粉体研究.重庆大学学报(自然科学 版),1999.22(1):95～98
[178] 刘继富,吴厚政,谈家琪等.冷冻干燥法制备MO-ZrO_2超细粉末.硅酸盐学报,1996.24(1):105～108
[179] 黄志良.溶胶—凝胶法合成羟基磷灰石的热稳定性研究.武汉化工学院学报,2002.24(2):
[180] 王欣宇,韩颖超.李世普.羟基磷灰石超微粉的柠檬酸盐法合成及表征.见:中国材料学会.2002年材料科学与工程新进展(下).北京:中国材料学会,2002.1467～1470
[181] 芮静安.肝癌治疗进展和展望.临床肝胆病杂志,2004.20(3):131～133
[182] 陈瑞铭,朱德厚,叶秀珍等.人体肝癌体外细胞系Bel-7402的建立及其特征.实验生物学报,1978.11(1):37
[183] 叶秀珍,朱德厚,沈鼎武.体外连续培养的肝细胞的超显微结构.实验生物学报.1980.13(4):362～365
[184] Mosmann T. Rapid colorimetic for cellular growth and survival:Application to proliferation and cytotoity assays. Immounol Methed, 1983.65:55
[185] 韩锐.抗癌药物研究与实验技术.北京:北京医科大学和中国协和医科大学联合出版社.1999.282～283,283～284,281～287
[186] 任玮玮.三氧化二砷对肝癌细胞株BEL-7402和SMMC-7721的作用及机制探讨:[硕士学位论文].广州:暨南大学,2003.14
[187] Chen RM. The establishment of a strain of human liver cell carcinoma in vitro and some preliminary observations. China Med J, 1963.82:228
[188] Bauscher, J. and W. I. Schaeffer. A diploid rat liver cell culture. I. Characterization and sensitivity to Aflatoxin B_1 In vitro, 1974.9:286～293
[189] Demoise C. F. et al. Tissue culture of adult human liver. Gastroenterology,1971.60:390～399
[190] 谭鲁鲁,周柔丽.医学细胞生物学.北京:北京医科大学和中国协和医科大学联合出版社,1992.198～204
[191] 罗琦.新型砷化物药敏性试验研究:[硕士学位论文].重庆:重庆大学,2003.18～25
[192] 唐胜利,袁媛,刘志苏等.羟基磷灰石纳米粒子对人肝癌BEL-7402细胞毒性的评价.肝脏,2003.8(1):21～24
[193] Zhi-Su Liu, Sheng-Li Tang, Zhing-Li Ai. Effects of hydroxyapatite nanoparticles on proliferation and apoptosis of human hepatoma BEL-7402 cells. World J Gastroenterol, 2003.9(9):1968～1971
[194] 应国华.电镜技术与细胞超微结构.香港:香港现代出版社,1993.31～50
[195] 韩颖超,李世普,曹献英等.冷冻干燥法制备纳米经基磷灰石粉体.见:中国材料学会. 纳米材料和技术应用进展——全国第三届纳米材料和技术应用会议论文集(上卷).南京:中国材料学会,2003.114～117
[196] 吴应荣,巢志瑜,潘巨祥.同步辐射微探针荧光分析.光谱实验室,1998.15(1):13～19
[197] 杜正通,黄东标,凌志强.顺铂诱导人骨肉瘤细胞凋亡及其分子机制的初步研究.中国误诊学杂志,2003.3(3):329～331
[198] Jens Meyer, Andreas F. Mack. Anthony W. Gummer. Pronounced infracuticular endocytosis in mammalian outer hair cells. Hearing Research, 2001. 161:10～22
[199] D. Dufrace, O. Cornu, C. Delloye, et al. Physical and chemical processing for a human dura mater substitute. Biomaterials, 2002.23:2979～2988
[200] Terasaki M. Labeling of the Endoplasmic Reticulum with DiO_6(3). Cell Biology: A Laboratory Handbook. Celis JE. Ed., 1998.501～506
[201] 戴维德,王雷,刘凡光等.应用激光扫描共聚焦显微成像术研究光敏剂亚细胞定位.中国激光医学杂志,2004.13(1):12～17
[202] Yuping Gong, Yanting Wang, Fanyuan Chen, et al. Identification of the subcellular localization of daunorubicin in multidrug-resistant K562 cell line. Leukemia Research, 2000.24:769～774
[203] 任卫.反相微乳液法制备纳米羟基磷灰石的研究:[博士学位论文].武汉:武汉理工大学,2003.70～88
[204] Tanaka H, Nuno Y, Irie S. Adsorption mechanism of poly-lysine on hydroxyapatite and its effect on dissolution properties of hydroxyapatite. Talanta,1992.39(8):893～898
[205] 吴应荣,巢志瑜等.怀孕期头发中一些元素含量的变化趋势.光谱学与光谱分析,1992.12(6):99～102
[206] Qian Q F, Feng W Y, et al. Study on the Effect of Supplementation of Iron-Fortied Food to Chinese Juvenile Athletes by Nuclear Analysis Technigues and Analysis J Radioanal. Nul. Chem. Letters, 1996.212(1):51～59
[207] 郑树,陈丽荣等.同步辐射对直肠癌组织微量元素测定的意义探讨.科技通报,1994.10(1):1～5
[208] 李楠.激光扫描共聚焦显微术.北京:人民军医出版社,1997.3～7
[209] 章静波.细胞生物学实用方法与技术.北京:北京医科大学和中国协和医科大学联合出版社,1995.
[210] 冯树,张福会,苏岩平等.培养的不同分化程度的人大肠癌细胞内质网结构特点.中国医科大学学报,2000.29(3):161～163
[211] Terasaki M., Song J, Wong J R, et al. Localization of endoplasmic reticulum on living and glutaraldehyde fixed cells with fluorescence dyes. Cell, 1984.38:101～108
[212] Toshihiko Tsutsumi, Akiro Tokumura, Shikifumi Kitazawa. Undifferentiated HL-6O cells internalize an antitumor alkyl ether phospholipid more rapidly than resistant K562 cells. Biochimica et Biophysica Acta, 1998.1390:73～84
[213] 汤钊猷,余业勤.原发性肝癌.上海:上海科学技术出版社,1999.362～371
[214] 蔡筱彦.凋亡素基因转入人类肝癌细胞诱导细胞凋亡研究:[硕士学位论文].广州:暨南大学,2002.11
[215] 谢冰芬,冯公侃,朱孝峰等.茶多酚对人癌细胞和人体细胞增殖及凋亡的实验研究.中草药,2003.6:540～543
[216] CAO Xian-ying, LI Shi-pu, ZHANG Ran, et al. Effect on the Hepatocellular Carcinoma Cell Proliferation and Cell Cycle Treated with Hydroxyapatite Nanoparticles. CttINA J CANCER PREV TREAT, 2003. 10(3):256～258
[217] 许迅辉,王国民,任豫申.应用吖啶橙染色法检查尿液癌细胞的评价.国外医学临床生物化学与检验学分册,2001.22(4):220
[218] George P, Han J, Watnab T, et al. Quantitative fluorescence measurements of AO stained normal and malignant bladder cells, Int J Cancer, 1983. 31:577
[219] 张覃沐.抗肿瘤药物的药理与临床应用.郑州:河南医科大学出版社,1999.10～14
[220] Shao JC, Wu JF, Wang DB, et al. Relationship between the expression of human telomerase reverse transcriptase gene and cell cycle regulators in gastric cancer and its significance. World J Gastroenterol, 2003.9(3):427～431
[221] 吴波,周晓军.细胞凋亡的检测方法.临床与实验病理学杂志.1997.13(3):262～263
[222] 云径平,林汉良,吴秋良.食管小细胞癌的临床病理、免疫组化及电镜观察.癌症,1998.17(4):251～253
[223] 胡军祥,虞研原,葛云法.肿瘤细胞深低温冷冻后的功能和超微结构变化的研究.科技通报,1995.11(6):341～346
[224] 魏文,冯宇霞,张双喜等.吖啶橙与碘化丙啶检测细胞DNA方法的比较.中华物理医学杂志,1994.16(3):166～169
[225] Ying Wang, Xianting Li, Lu Wang, et al. An alternative form of paraptosis-like cell death, triggered by TAJ/TROY and enhanced by PDCD5 overexpression. Journal of Cell Science, 117(8): 1525～1532
[226] Asher E, Payne CM, Bernstein C. Evaluation of cell death in EBV-transfonned lymphocytes using agarose gel electrophresis,light microscopy and electron microscopy. Ⅱ Induction of non-classic apoptosis(para-apoptosis) by tritiaied thymidine. leuk lymphoma, 1995.19(1-2):107～119
[227] Kitanaka C, Kuchino Y. Caspase independent programmed cell death with necrotic orphology. Cell Death Differ, 1999.6(6):508～515
[228] Lorenzen J, thiele J, Fischer R. The mummified Hodgkin: cell death in Hodgkin's eisease. J Pathol, 1997.182:288～298
[229] Sabina Sperandio, Ian de Belle, Dale E. Bredesen. An alternative, nonapoptotic form of programmed cell death. Cell Biology,2000. 97(26): 14376～14381
[230] Forcet C, Ye X, Granger L, et al. The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation. PNA S,2001.98(6):3416～3421
[231] Jacobson M D, Weil M, Raff M C. Programmed cell death in animal development. Cell, 1997.88(3):347～35
[232] 孙靖中,邹雄.肿瘤分子生物学.北京:人民卫生出版社,1998.142～144
[233] HeTc, SparksAb, Ragoc, et al. Indentic c-myc as a targetgene of APC. Science, 1998, 282:1499～1513
[234] Skouteris GG, Schroder CH. C-myc is required for the G_0/G_1-stransition of primary hepatocytes stimulated with a deleted form of hepatocytes growth factor. Biochem,1996.316:879～886
[235] Caelles C, Heimberg A, Karin M. A new function for p53 in poptosis. Trends Cell Biol, 1994.4:356-364