化疗药物细胞周期特异性的重新评估
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摘要
目的:由于技术限制,此前还较少有人直观地展现非同步化条件下化疗药物诱导细胞凋亡的细胞周期特异性。但是,细胞周期同步化被证明是对细胞状态的一种干扰,可能导致“假象”研究结果。在这部分研究中,我们将首先建立化疗药物作用于对数生长期细胞系的细胞周期特异性检测模型。
方法:以处于对数生长期的人类急性淋巴细胞性白血病细胞系(MOLT-4细胞)为研究对象,分别用喜树碱(CPT)、阿糖胞苷(Ara-C)、替尼泊甙(VM-26)、甲氨蝶呤(MTX)、泰素(Taxol)、长春新碱(VCR)等常用细胞周期特异性化疗药物(Cell-cycle specific agents, CCSA)以不同剂量、不同作用时间加以处理,以API法检测细胞凋亡的细胞周期特异性。以分选后激光共聚焦荧光显微镜技术对API法的结果加以进一步验证。从而比较观察出各种药物诱导细胞周期特异性凋亡的最佳条件,为进一步研究建立模型。
结果:CCSA作用于对数生长期的细胞系,在较低浓度及较短时间内仅引起细胞周期阻滞效应或(和)少量细胞周期特异性凋亡,在一定浓度及作用时间范围内出现明显的细胞周期特异性凋亡,超出这个范围后,往往引起广泛的无周期特异性的细胞死亡。喜树碱0.2μg/ml,阿糖胞苷100μg/ml,替尼泊甙50μg/ml,甲氨蝶呤40μg/ml作用4-6小时出现S期特异性凋亡;泰素1μg/ml、长春新碱1μg/ml作用9小时出现G2/M期凋亡。
结论:CCSA诱导的典型的早期细胞周期特异性凋亡在一定条件范围内可被API技术检测。在以对数生长的Molt-4细胞为模型时,这种特异性与目前一般认为的一致。
目的:利用第一部分研究建立的研究模型,检测在靶细胞生长状态发生改变后,化疗药物诱导细胞凋亡的细胞周期特异性,探讨化疗药物作用于体内外肿瘤的细胞周期特异性有无改变。
方法:建立“高密度状态”培养的Molt-4细胞模型,观察药物引起的细胞周期特异性凋亡,比较其与以对数生长期模型的差异。在此基础上,以临床急性淋巴细胞性白血病为研究对象,观察药物在体内、外的不同效应。
结果:当作用于“高密度状态”的Molt-4细胞时,CPT、Ara-C、MTX、VM-26、VCR与Taxol诱导的细胞凋亡主要都集中于G0/G1期,少部分在S期。当作用于临床急性淋巴细胞性白血病标本时, CPT、Ara-C、MTX、VM-26与VCR诱导的细胞凋亡主要都集中于G0/G1期,少部分在S期,Taxol则在S期。在对一例进行初次化疗的急性淋巴细胞性白血病患者的观察中,发现单用阿糖胞苷诱导G0/G1期及少量S期特异性凋亡,阿糖胞苷联合泰素在体内诱导的细胞周期特异性凋亡与此相同。而这些结果与对数生长期模型都不相同。
结论:在体内外不同生长状态下,化疗药物诱导细胞凋亡的细胞周期特异性会发生改变。化疗药物作用于“高密度状态”的Molt-4细胞以及作用于临床急性淋巴细胞性白血病标本所诱导的凋亡的细胞周期特异性类似,而且与患者化疗时体内的结果相符,进一步证实“高密度状态”的Molt-4细胞是体外培养细胞系模拟体内条件的较佳模型。我们的发现同时还提示,目前常用的化疗药物细胞周期特异性分类表可能与药物在体内的实际效应存在较大出入,可能需要重新评估。
Object:Due to technical limitations, there was very few paper published directly exhibiting the drug-induced cell-cycle specific apoptosis by non-synchronous methods. But the cell cycle synchronization has been proved to disturb the cell growing status and might lead to pseudo results. In this part of present research, we will establish a model of exponentially growing molt-4 cells, to test the cell-cycle specificity of chemotherapeutic agent in vitro.
Methods: The human acute lymphocyte leukemia cell line molt-4 was cultured to an exponentially growing status. Six commonly used cell-cycle specific agents (CCSA), including camptothecin (CPT), cytarabine (Ara-C), teniposide (VM-26), methotrexate (MTX), vincristine (VCR) and paclitaxel (Taxol), were added into the cell culture at different concentrations and incubated for 4 to 9 hours respectively. The drug-induced cell-cycle specific apoptosis was detected by API assay. For further verification of the API assay, post-sorting laser scan confocal microscopy (PSC) was used.
Results: At very low concentration with very short period of incubating time, CCSAs only induced cell cycle blocking effect and very few cells went to apoptosis. At higher concentration with appropriate incubating period, typical cell-cycle specific apoptosis appeared. But at concentration even higher than that or with longer incubating time, cells commited to die in all phases of the cell cycle. 0.2μg/ml CPT, 100μg/ml Ara-C, 50μg/ml VM-26 and 40μg/ml MTX induced S phase specific apoptosis at 4-6 hours after the administration, 1μg/ml Taxol and 1μg/ml VCR induced G2/M phase specific apoptosis at 9 hours.
Conclusions: The cell-cycle specific apoptosis induced by CCSAs could be typically detected by the API assay under certain conditions. The cell-cycle specificities of the 6 tested drugs in exponential model were consistent with those of common belief.
Objects: Based on the result of the first part of this research, the cell-cycle specificities of chemotherapeutic agents were detected in models of different cell growing status. We wanted to know whether the specificity would be different or not under such condition.
Methods: The model of“high-density cultured”molt-4 cells was established and was compared with the exponential model. In order to observe the in vivo effect of CCSAs, the clinical specimens of acute lymphocyte leukemia cells (the ex vivo model) were used and a leukemia patient (the in vivo model) was investigated during her first time chemotherapy.
Results: When incubated with high-density cultured molt-4 cells, CPT, Ara-C, MTX, VM-26, VCR and Taxol all induced apoptosis mainly in G0/G1 phase with a small proportion in S phase. In the clinical specimens (ex vivo model), CPT, Ara-C, MTX, VM-26 and VCR again induced apoptosis mainly in G0/G1 phase with a small proportion in S phase, while Taxol only in S phase. During the first day of chemotherapy of the patient, Ara-C induced G0/G1 and a little S phase specific apoptosis. The result of Ara-C plus Taxol together in the second day was almost the same with the first day.
Conclusions: The cell-cycle specificity of CCSA might change in different growing status of the target cells. The cell-cycle specific apoptosis induced in high-density cultured molt-4 was similar to that in clinical specimens, and was also consistent with that in vivo. Our observation further confirmed that high-density cultured cell line might be a better model to mimic the in vivo effect than the exponential model. It also suggested that the current classification of cell-cycle specific agent might not suitable for in vivo application and might need to be reassessed.
方法:以处于对数生长期的人类急性淋巴细胞性白血病细胞系(MOLT-4细胞)为研究对象,分别用喜树碱(CPT)、阿糖胞苷(Ara-C)、替尼泊甙(VM-26)、甲氨蝶呤(MTX)、泰素(Taxol)、长春新碱(VCR)等常用细胞周期特异性化疗药物(Cell-cycle specific agents, CCSA)以不同剂量、不同作用时间加以处理,以API法检测细胞凋亡的细胞周期特异性。以分选后激光共聚焦荧光显微镜技术对API法的结果加以进一步验证。从而比较观察出各种药物诱导细胞周期特异性凋亡的最佳条件,为进一步研究建立模型。
结果:CCSA作用于对数生长期的细胞系,在较低浓度及较短时间内仅引起细胞周期阻滞效应或(和)少量细胞周期特异性凋亡,在一定浓度及作用时间范围内出现明显的细胞周期特异性凋亡,超出这个范围后,往往引起广泛的无周期特异性的细胞死亡。喜树碱0.2μg/ml,阿糖胞苷100μg/ml,替尼泊甙50μg/ml,甲氨蝶呤40μg/ml作用4-6小时出现S期特异性凋亡;泰素1μg/ml、长春新碱1μg/ml作用9小时出现G2/M期凋亡。
结论:CCSA诱导的典型的早期细胞周期特异性凋亡在一定条件范围内可被API技术检测。在以对数生长的Molt-4细胞为模型时,这种特异性与目前一般认为的一致。
目的:利用第一部分研究建立的研究模型,检测在靶细胞生长状态发生改变后,化疗药物诱导细胞凋亡的细胞周期特异性,探讨化疗药物作用于体内外肿瘤的细胞周期特异性有无改变。
方法:建立“高密度状态”培养的Molt-4细胞模型,观察药物引起的细胞周期特异性凋亡,比较其与以对数生长期模型的差异。在此基础上,以临床急性淋巴细胞性白血病为研究对象,观察药物在体内、外的不同效应。
结果:当作用于“高密度状态”的Molt-4细胞时,CPT、Ara-C、MTX、VM-26、VCR与Taxol诱导的细胞凋亡主要都集中于G0/G1期,少部分在S期。当作用于临床急性淋巴细胞性白血病标本时, CPT、Ara-C、MTX、VM-26与VCR诱导的细胞凋亡主要都集中于G0/G1期,少部分在S期,Taxol则在S期。在对一例进行初次化疗的急性淋巴细胞性白血病患者的观察中,发现单用阿糖胞苷诱导G0/G1期及少量S期特异性凋亡,阿糖胞苷联合泰素在体内诱导的细胞周期特异性凋亡与此相同。而这些结果与对数生长期模型都不相同。
结论:在体内外不同生长状态下,化疗药物诱导细胞凋亡的细胞周期特异性会发生改变。化疗药物作用于“高密度状态”的Molt-4细胞以及作用于临床急性淋巴细胞性白血病标本所诱导的凋亡的细胞周期特异性类似,而且与患者化疗时体内的结果相符,进一步证实“高密度状态”的Molt-4细胞是体外培养细胞系模拟体内条件的较佳模型。我们的发现同时还提示,目前常用的化疗药物细胞周期特异性分类表可能与药物在体内的实际效应存在较大出入,可能需要重新评估。
Object:Due to technical limitations, there was very few paper published directly exhibiting the drug-induced cell-cycle specific apoptosis by non-synchronous methods. But the cell cycle synchronization has been proved to disturb the cell growing status and might lead to pseudo results. In this part of present research, we will establish a model of exponentially growing molt-4 cells, to test the cell-cycle specificity of chemotherapeutic agent in vitro.
Methods: The human acute lymphocyte leukemia cell line molt-4 was cultured to an exponentially growing status. Six commonly used cell-cycle specific agents (CCSA), including camptothecin (CPT), cytarabine (Ara-C), teniposide (VM-26), methotrexate (MTX), vincristine (VCR) and paclitaxel (Taxol), were added into the cell culture at different concentrations and incubated for 4 to 9 hours respectively. The drug-induced cell-cycle specific apoptosis was detected by API assay. For further verification of the API assay, post-sorting laser scan confocal microscopy (PSC) was used.
Results: At very low concentration with very short period of incubating time, CCSAs only induced cell cycle blocking effect and very few cells went to apoptosis. At higher concentration with appropriate incubating period, typical cell-cycle specific apoptosis appeared. But at concentration even higher than that or with longer incubating time, cells commited to die in all phases of the cell cycle. 0.2μg/ml CPT, 100μg/ml Ara-C, 50μg/ml VM-26 and 40μg/ml MTX induced S phase specific apoptosis at 4-6 hours after the administration, 1μg/ml Taxol and 1μg/ml VCR induced G2/M phase specific apoptosis at 9 hours.
Conclusions: The cell-cycle specific apoptosis induced by CCSAs could be typically detected by the API assay under certain conditions. The cell-cycle specificities of the 6 tested drugs in exponential model were consistent with those of common belief.
Objects: Based on the result of the first part of this research, the cell-cycle specificities of chemotherapeutic agents were detected in models of different cell growing status. We wanted to know whether the specificity would be different or not under such condition.
Methods: The model of“high-density cultured”molt-4 cells was established and was compared with the exponential model. In order to observe the in vivo effect of CCSAs, the clinical specimens of acute lymphocyte leukemia cells (the ex vivo model) were used and a leukemia patient (the in vivo model) was investigated during her first time chemotherapy.
Results: When incubated with high-density cultured molt-4 cells, CPT, Ara-C, MTX, VM-26, VCR and Taxol all induced apoptosis mainly in G0/G1 phase with a small proportion in S phase. In the clinical specimens (ex vivo model), CPT, Ara-C, MTX, VM-26 and VCR again induced apoptosis mainly in G0/G1 phase with a small proportion in S phase, while Taxol only in S phase. During the first day of chemotherapy of the patient, Ara-C induced G0/G1 and a little S phase specific apoptosis. The result of Ara-C plus Taxol together in the second day was almost the same with the first day.
Conclusions: The cell-cycle specificity of CCSA might change in different growing status of the target cells. The cell-cycle specific apoptosis induced in high-density cultured molt-4 was similar to that in clinical specimens, and was also consistent with that in vivo. Our observation further confirmed that high-density cultured cell line might be a better model to mimic the in vivo effect than the exponential model. It also suggested that the current classification of cell-cycle specific agent might not suitable for in vivo application and might need to be reassessed.
引文
1. Vincent T Devita et al. Cancer: Principles & Practice of Oncology, 6th ed. 2001.
2. Debatin KM. Activation of apoptosis pathways by anticancer drugs. Adv Exp Med Biol. 1999; 457:237-244.
3. Marchall EK Jr. Historical perspectives in chemotherapy. Adv Chemother, 1964; 13:1-8.
4. Robert C et al. Cancer Medicine, 5th ed. 2000.
5. Charles M. Haskell, Cancer Treatment, 5th ed. 2001.
6. Derek Crowther, Cancer Chemotherapy, in Treatment of Cancer, Chapter 17:p74, Keith E. Halnan eds, London, 1982.
7. Hartwell LH and Kastan KB. Cell cycle control and cancer. Science, 1994; 266:1821-1828.
8. Hunter T and Pines J. Cyclins and cancers. Cell, 1991; 66:1071-1074.
9. Annie Borgne and Roy M. Golsteyn, The Role of Cyclin-Dependent Kinase in Apoptosis, in Progress in Cell cycle Research, Vol. 5, chapter 46:p453-459, Meijer L., Jezequel A., and Roberge M. eds, 2003.
10. J Gong, U Bhatia, F Traganos and Z Darzynkiewicz, Expression of cyclins A, D2 and D3 in individual normal mitogen stimulated lymphocytes and in MOLT-4 leukemic cells analyzed by multiparameter flow cytometry. Leukemia, 1995; 9:893-899.
11. JP Gong, F Traganos and Z Darzynkiewicz, Expression of cyclins B and E in individual MOLT-4 cells and in stimulated human lymphocytes during their progression through the cell cycle. Int J Oncol, 1993; 3: 1037-1042.
12. JP Gong, F Traganos and Z Darzynkiewicz, Growth Imbalance and altered expression of cyclins B1, A, E, and D3 in MOLT-4 cells synchronized in the cell cycle by Inhibitors of DNA replication. Cel Grow & Diff, 1995; 6:1485-1493.
13. 吴剑宏,细胞周期调控细胞凋亡的研究,华中科技大学同济医学院博士学位论文,2003。
14. 冯永东,细胞凋亡与细胞周期的协同及分子机制研究,华中科技大学同济医学院博士学位论文,2004。
15. 谢大兴,人类在体增殖细胞的细胞周期调控机制,华中科技大学同济医学院博士学位论文,2005。
1. Debatin KM. Activation of apoptosis pathways by anticancer drugs. Adv Exp Med Biol. 1999; 457:237-244.
2. Boyd MR. Status of the NCI preclinical antitumor drug discovery screen. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology Updates, vol. 3, no. 10. Philadelphia: Lippincott. 1989:1-12.
3. Skipper HE, Schabel FM Jr, Wilcox WS. Experimental evaluation of potential anticancer agents. XXI. Scheduling of arabinosylcytosine to take advantage of its S-phase specificity against leukemia cells. Cancer Chemother Rep 1967; 51:125-165.
4. Li LH, Olin EJ, Fraser TJ, Bhuyan BK. Phase specificity of 5-Azacytidine against mammalian cells in tissue culture. Cancer Res 1970; 30:2770-2775.
5. Li LH, Fraser TJ, Olin EJ, Bhuyan BK. Action of camptothecin on mammalian cells in culture. Cancer Res 1972; 32:2643-2650.
6. Hennequin C, Giocanti N, Favaudon V. S-phase specificity of cell killing by docetaxel (Taxotere) in synchronized HeLa cells. Br J Cancer 1995; 71:1194-1198.
7. Stephen EM, Hidemi S, Klaus GB. Vinblastine and griseofulvin reversibly disrupt the living mitotic spindle. Science 1968; 160:770-771.
8. Tao D, Wu J, Feng Y, Qin J, Hu J, Gong J. New method for the analysis of cell cycle-specific apoptosis. Cytometry. 2004; 57A(2): 70-74.
9. Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, Green DR. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med 1995; 182: 1545-1556.
10. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972; 26(4): 239-257.
11. Arends MJ, Morris RG, Wyllie AH. Apoptosis. The role of the endonuclease. Am J Pathol. 1990; 136(3): 593-608.
12. Gong J, Traganos F, Darzynkiewicz Z. A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry. Anal Biochem. 1994; 218(2): 314-319.
13. Olive PL, Banath JP, Durand RE. Heterogeneity in radiation-induced DNA damage and repair in tumor and normal cells measured using the "comet" assay. Radiat Res. 1990; 122(1): 86-94.
14. Gorczyca W, Gong J, Darzynkiewicz Z. Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assays. Cancer Res. 1993; 53:1945-1951.
15. Smolewski P, Grabarek J, Halicka HD, Darzynkiewicz Z. Assay of caspase activation in situ combined with probing plasma membrane integrity to detect three distinct stages of apoptosis. J Immunol Methods. 2002; 265: 111-121.
16. Castedo M, Hirsch T, Susin SA, Zamzami N, Marchetti P, Macho A, Kroemer G. Sequential acquisition of mitochondrial and plasma membrane alterations during early lymphocyte apoptosis. J Immunol 1996; 157(2): 512-521.
17. Donehower RC, Karp JE, Burke PJ. Pharmacology and toxicity of high-dose cytarabine by 72-hour continous infusion. Cancer Treat Rep 1986; 70(9): 1059-1065.
18. Capizzi RL, White JC, Powell BL, Perrino F. Effect of dose on the pharmacokinetic and pharmacodynamic effects of cytarabine. Seminars Hematol 1991; 28(Suppl 4): 54-69.
19. Vincent T Devita et al. Cancer: Principles & Practice of Oncology, 6th ed. Philadelphia: Lippincott. 2001.
20. Huizing MT, Keung ACF, Rosing H, et al. Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol 1993; 11(11): 2127-2135.
21. Gianni L, Kearns CM, Giani A, Capri G, Vigano L, Lacatelli A, Bonadonna G, Egorin MJ. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetics/pharmacodynamic relationships in humans. J Clin Oncol 1995; 13(1): 180-190.
22. Rowinsky EK, Donehower RC. The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics. Pharmacol Ther 1991; 52(1): 35-84.
1. 岳东方,1901-2004 年诺贝尔奖得主及其所属单位,生命科学,2004;16(6):421-430。
2. David R. Hipfner and Stephen M. Cohen. Connecting proliferation and apoptosis in development and disease. Nature Rev Mol Cel Bio 2004; 5: 805-815.
3. Annie B and Roy MG, The Role of Cyclin-Dependent Kinase in Apoptosis, in Progress in Cell cycle Research, Vol. 5, chapter 46:p453-459, Meijer L., Jezequel A., and Roberge M. eds, 2003.
4. J Gong, U Bhatia, F Traganos and Z Darzynkiewicz, Expression of cyclins A, D2 and D3 in individual normal mitogen stimulated lymphocytes and in MOLT-4 leukemic cells analyzed by multiparameter flow cytometry. Leukemia, 1995; 9:893-899.
5. JP Gong, F Traganos and Z Darzynkiewicz, Expression of cyclins B and E in individual MOLT-4 cells and in stimulated human lymphocytes during their progression through the cell cycle. Int J Oncol, 1993; 3: 1037-1042.
6. JP Gong, F Traganos and Z Darzynkiewicz, Growth Imbalance and altered expression of cyclins B1, A, E, and D3 in MOLT-4 cells synchronized in the cell cycle by Inhibitors of DNA replication. Cel Grow & Diff, 1995; 6:1485-1493.
7. 谢大兴,人类在体增殖细胞的细胞周期调控机制,华中科技大学同济医学院博士学位论文,2005。
8. Dustin P. The centennial of the discovery of the antimitotic properties of colchicines. Rev Med Brux. 1989; 10(9): 385-90.
9. T. J. Mitchison and E. D. Salmon. Mitosis: a history of division. Nature Cel Biol 2001; 3:17-21.
10. Boyd MR. Status of the NCI preclinical antitumor drug discovery screen. PPO Updates, 1989; 8:1.
11. Skipper HE, Schabel FM, Wilcox WS. Experimental evaluation of potential anti-cancer agents. XII. On the criteria and kinetics associated with “curability” of experimental leukemia. Cancer Chemother Rep 1964; 35:1.
12. Brown JM, Wouters BG. Does apoptosis contribute to tumer cell sensitivity toanticancer agents? In Cancer Drug Discovery and Development Series: Apoptosis and Cancer Chemotherapy, chapter 1:p12-13, John AH and Caroline D eds, 1999.
13. Nadim Jessani, Sherry Niessen, Barbara M. Mueller, Benjamin F. Cravatt. Breast Cancer Cell Lines Grown in Vivo What Goes in Isn’t Always the Same as What Comes Out. Cell Cycle 2005; 4(2): 253-255.
14. Bin-Bing S. Zhou, Stephen J. Elledge. The DNA damage response: putting checkpoints in perspective. Nature, 2000; 408(23): 433-439.
15. Iliakis G, Ya W, Jun G and Huichen W. DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene, 2003; 22: 5834-5847.
16. J Bartek, C Lukas and J Lukas. Checking on DNA damage in S phase. Nature Rev Mol Cel Bio 2004; 5: 792-804.
17. 吴剑宏,细胞周期调控细胞凋亡的研究,华中科技大学同济医学院博士学位论文,2003。
18. 冯永东,细胞凋亡与细胞周期的协同及分子机制研究,华中科技大学同济医学院博士学位论文,2004。
19. Lisa AP, Gurmit S and Jonathan ML. Abundance of cyclin B1 regulates g-radiation-induced apoptosis. Blood. 2000; 95: 2645-2650.
20. Bin-Bing Z, Hong LL, Jun YY and Marc WK. Caspase-dependent activation of cyclin-dependent kinases during Fas-induced apoptosis in Jurkat cells. PNAS 1998; 95: 6785–6790.
21. L. Shi, W.K. Niskioka, J. Th'ng, E.M. Bradbury, D.W. Litchfield, A.H. Greenberg, Premature p34cdc2 activation required for apoptosis, Nature 1994; 263: 1143-1145.
22. L. Shi, G. Chen, D. He, D.G. Bosc, D.W. Litchfield, A.H. Greenberg, Granzyme B induces apoptosis and cyclin A-associated cyclin-dependent kinase activity in all stages of the cell cycle, J. Immunol. 157 (1996) 2381-2385.
23. Hiromura K, Pippin JW, Blonski MJ, Roberts JM, Shankland SJ. The subcellular localization of cyclin dependent kinase 2 determines the fate of mesangial cells: role in apoptosis and proliferation. Oncogene 2002; 21: 1750-1758.
24. K Hiromural, JW Pippin, MJ Blonskil, JM Roberts and SJ Shankland. Thesubcellular localization of cyclin dependent kinase 2 determines the fate of mesangial cells role in apoptosis and proliferation. Oncogene 2002; 21: 1750-1758.
25. Anne Hakem, Takehiko Sasaki, Ivona Kozieradzki, and Josef M. Penninger The Cyclin-dependent Kinase Cdk2 Regulates Thymocyte Apoptosis. J. Exp. Med.
26. Katrien Vermeulen, Zwi N. Berneman and Dirk R. Van Bockstaele. Cell cycle and apoptosis. Cell Prolif. 2003; 36:165–175.
27. Abrams JM, White MA. Coordination of cell death and the cell cycle: linking proliferation to death through private and communal couplers. Cur Opin Cel Bio 2004; 16:634–638.
28. Halicka HD, Seiter K, Feldman EJ, Traganos F, Mittelman A, Ahmed T, Darzynkiewicz Z. Cell cycle specificity of apoptosis during treatment of leukaemias. Apoptosis 1997; 2: 25-39.
1.现代肿瘤治疗药物学,廖子君等主编。-西安:世界图书出版西安公司,2002.2.
2.Handbook of Cancer Chemotherapy (5th edition), Roland T. Skeel, 1999. -p8
3.Cancer Treatment (5th edition), Charles M. Haskell, 2001. -p104
4.Clinical Oncology (2nd edition), Abeloff MD, 1999.
5.血液肿瘤学,沈志祥等主编,-北京:人民卫生出版社,1999.-p57
1. Kerr JFR, Wyllie AH, Curie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239-257.
2. 岳东方,1901-2004 年诺贝尔奖得主及其所属单位,生命科学,2004;16(6):421-430。
3. Guimaraes C A, Linden R. Programmed cell death Apoptosis and alternative deathstyles. Eur J Biochem. 2004; 271:1638-1650.
4. Degterev A, Huang Z, Boyce M et al. Chemical inhibitor of nonapoptotic death with therapeutic potential for ischemic brain injury. Nat Chem Biol 2005; 1(2): 112-119.
5. Fiers W, Beyaert R, Declercq W, Vandenabeele P. More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene 1999; 18: 7719-7730.
6. Zeiss CJ. The Apoptosis-Necrosis Continuum: Insights from Genetically Altered Mice. Vet Pathol 2003; 40:481-495.
7. 兰蕾,赫荣乔。细胞周期分子机制的成功探索-2001 年诺贝尔生理及医学奖部分工作介绍。生物化学与生物物理进展,2001; 28: 773-777。
8. Qin JC, Tao DD, Duan R, Leng Y, Shen ML, Zhou H, Feng YD, Gao C,Yu Y, Li QD, Hu JB, Gong JP. Cytokinetic analysis of cell cycle and sub-phases in MOLT-4 cells by cyclin E + A/DNA multiparameter flow cytometry. Oncol Rep 2002; 9: 1041-1045.
9. Borgne A, Golsteyn RM. The role of cyclin-dependent kinases in apoptosis. In: Meijer L, Jezequel A, Roberge M, ed. Progress in Cell Cycle Research, 2003; 5: 453-459.
10. Hipfner DR, Cohen SM. Connecting proliferation and apoptosis in development and disease. Nat Rew Mol Cell Biol 2004; 5: 805-815.
11. Alenzi FQB. Links between apoptosis, proliferation and the cell cycle. Br J Biomed Sci 2004; 61(2): 99-102.
12. Nahle Z, Polakoff J, Davuluri RV, McCurrach ME, Jacobson MD, Narita M, Zhang MQ, Lazebnik Y, Bar-Sagi D, Lowe SW. Direct coupling of the cell cycle and cell death machinery by E2F. Nat Cell Biol 2002; 4:859-864.
13. Gil-Gomez G, Berns A, Brady HJM. A link between cell cycle and cell death Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis. EMBO J 1998; 17(24): 7209-7218.
14. Vermeulen K, Berneman ZN, Van Bockstaele DR. Cell cycle and apoptosis. Cell Prolif, 2003,36:165-175.
15. Chapter 18. Cell-Cycle Control and apoptosis. In: Alberts B, Johnson A, Lewis J et al. ed. Essential Cell Biology, 2nd edition. New York: Garland Science/Taylor & Francis Group, 2003; 612-636.
16. Pardee AB. G1 events and regulation of cell proliferation. Science 1989; 246:603-608.
17. 龚建平,第六章 细胞周期与肿瘤。曾益新主编,肿瘤学,北京:人民卫生出版社,1999。
18. Iliakis G, Ya W, Jun G and Huichen W. DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene, 2003; 22: 5834-5847.
19. Degterev A, Boyce M, Yuan J. A decade of caspases. Oncogene 2003; 22: 8543-8567.
20. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis - the p53 network. Journal of Cell Science, 2003; 116: 4077-4085.
21. Nagata S. Apoptosis by death factor. Cell 1997; 88: 355-365.
22. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli K, Debatin K-M, Krammer PH, Peter ME. Two CD95 (APO-1 Fas) signaling pathways. The EMBO Journal, 1998; 17(6): 1675-1687.
23. Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 2003; 22: 8608-8618.
24. Kawahara A, Ohsawa Y, Matsumura H, Uchiyama Y, Nagata S. Caspase-independent cell killing by Fas-associated protein with death domain. Journal of Cell Biology 1998; 143:1353-1360.
25. Kitanaka C, Kuchino Y. Caspase-independent programmed cell death with necrotic morphology. Cell Death and Differentiation 1993; 6: 508-515.
26. Green DR. Apoptotic pathways: ten minutes to death. Cell 2005; 121: 671-674.
27. Green DR, Amarante-Mendes GP. The point of no return. Results Probl Cell Differ. 1998; 24: 45-61.
28. Shi L, Niskioka WK, Th'ng J, Bradbury EM, Litchfield DW, Greenberg AH. Premature p34cdc2 activation required for apoptosis. Nature 1994; 263: 1143-1145.
29. Bin-Bing Z, Hong LL, Jun YY and Marc WK. Caspase-dependent activation of cyclin-dependent kinases during Fas-induced apoptosis in Jurkat cells. PNAS 1998; 95: 6785–6790.
30. Harvey KJ, Lukovic D, Ucker DS. Caspase-dependent Cdk activity is a requisite effector of apoptotic death events. J Cell Biol. 2000; 148: 59-72.
31. Meikrantz W, Schlegel R. Suppression of apoptosis by dominant negative mutants of cyclin-dependent protein kinases, J. Biol. Chem. 21996; 71: 10205-10209.
32. Sandal T, C Stapnes, Kleivdal H, Hedin L, Doskeland SO. A novel, extraneuronal role for cyclin-dependent protein kinase (CDK5). Modulation of cAMP-inducedapoptosis in rat leukemia cells. J. Biol. Chem. 2002; 277: 20783-20793.
33. Kim SG, Kim SN, Jong HS, Kim NK, Hong SH, Kim SJ, Bang YJ. Caspase-mediated Cdk2 activation is a critical step to execute transforming growth factor-beta1-induced apoptosis in human gastric cancer cells. Oncogene 2001; 20: 1254-1265.
34. Hsu S, Yin S, Liu M, Reichert U, Ho WL. Involvement of cyclin-dependent kinase activities in CD437-induced apoptosis. Exp Cell Res 1999; 252: 332-341.
35. L. Shi, G. Chen, D. He, D.G. Bosc, D.W. Litchfield, A.H. Greenberg, Granzyme B induces apoptosis and cyclin A-associated cyclin-dependent kinase activity in all stages of the cell cycle, J. Immunol. 1996; 157: 2381-2385.
36. Gil-Gomez G, Berns A, Brady HJM. A link between cell cycle and cell death: Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis. The EMBO Journal. 1998; 17(24): 7209-7218.
37. Shen M, Feng Y, Gao C, Tao D, Hu J, Reed E, Li Q, Gong J. Detection of Cyclin B1 Expression in G1-Phase Cancer Cell Lines and Cancer Tissues by Postsorting Western Blot Analysis. Cancer Res 2004; 64: 1607–1610.
38. 冯永东,细胞凋亡与细胞周期的协同及分子机制研究,华中科技大学同济医学院博士学位论文,2004。
39. Shimizu T, O'Connor PM, Kohn K, Pommier Y. Unscheduled activation of cyclinB1/cdc2 kinase in human promyelocytic leukemia cell line HL60 cells undergoing apoptosis induced by DNA damage, Cancer Res. 1995; 55: 228-231.
40. Hahntow IN, Schneller F, Oelsner M, Weick K, Ringshausen I, Fend F, Peschel C, Decker T. Cyclin-dependent kinase inhibitor roscovitine induces apoptosis in chronic lymphocytic leukemia cells. Leukemia 2004; 18: 747-755.
41. Lane ME, Yu B, Lipson KE, Liang C, Sun L, Tang C, McMahon G, Pestell RG, Wadler S. A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells. Cancer Res. 2001; 61: 6170-6177.
42. Park DS, Farinelli SE, Greene LA. Inhibitors of cyclin-dependent kinases promote survival of post-mitotic neuronally differentiated PC12 cells and sympathetic neurons. J Biol Chem 1996; 271: 8161-8169.
43. Konishi Y, Lehtinen M, Donovan N, Bonni A. Cdc2 phosphorylation of Bad links the cell cycle to the cell death machinery. Mol Cell 2002; 9: 1005-1016.
44. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X (L). Cell 1996; 87: 619-628.
45. Hollstein M, Sidransky D, Vogelstein B, Hanis CC. p53 mutations in human cancers. Science 1991; 253:49-53.
46. Mutoh M, Lung FDT, Long YQ, Roller PP, Sikorski RS, O'Connor PM. A p21Waf1/Cip1 carboxyl-terminal peptide exhibited cyclin-dependent kinase inhibitory activity and cytotoxicity when introduced into human cells. Cancer Res. 1999; 59: 3480-3488.
47. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995; 81(3): 323-30.
48. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997; 88: 323-331.
49. Bunz F, Dutriaux H, Lengauer C, Waldman T, Zhou S, Brown J P, Sedivy JM, Kinzler KW, Vogelstein B. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science. 1998; 282: 1497-1501.
50. Ford JM. Regulation of DNA damage recognition and nucleotide excision repair: another role for p53. Mutation Research. 2005; 577: 195-202.
51. Fridman JS, Lowe SW. Control of apoptosis by p53. Oncogene. 2003; 22: 9030-9040.
52. Tao W, Levine AJ. Nucleocytoplasmic shuttling of oncoprotein Mdm2 is required for Mdm2-mediated degradation of p53. Proc Natl Acad Sci USA 1999; 96: 3077-3080.
53. Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature 1997; 387: 299-303.
54. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature 1997; 387: 296-299.
55. Fuchs SY, Adler V, Buschmann T, Wu X, Ronai Z. Mdm2 association with p53targets its ubiquitination. Oncogene 1998; 17: 2543-2547.
56. Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev 1993; 7: 1126-1132.
57. Cory S, Huang DCS, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003; 22: 8590-8607.
58. Bouillet P, Purton JF, Godfrey DI, Zhang L-C, Coultas L, Puthalakath H, Pellegrini M, Cory S, Adams JM and Strasser A. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature, 2002; 415(6874): 922-926.
59. Hildeman DA, Zhu Y, Mitchell TC, Bouillet P, Strasser A, Kappler J and Marrack P. Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. Immunity, 2002; 16(6): 759-767.
60. Bouillet P, Metcalf D, Huang DCS, Tarlinton DM, Kay TWH, Frank K?ntgen F, Adams JM and Strasser A. Proapoptotic Bcl-2 Relative Bim Required for Certain Apoptotic Responses, Leukocyte Homeostasis, and to Preclude Autoimmunity. Science. 1999; 286: 1735–1738.
61. Danial NN, Gramm CF, Scorrano L, Zhang CY, Krauss S, Ranger AM, Datta SR, Greenberg ME, Licklider LJ, Lowell BB, Gygi SP and Korsmeyer SJ. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature. 2003; 424(6951): 952-956.
62. Ranger AM, Zha J, Harada H, Datta SR, Danial NN, Gilmore AP, Kutok JL, Le Beau MM, Greenberg ME and Korsmeyer SJ. Bad-deficient mice develop diffuse large B cell lymphoma. Proc. Natl. Acad. Sci. USA, 2003; 100: 9324–9329.
63. Puthalakath H, Villunger A, O’Reilly LA, Beaumont JG, Coultas L, Cheney RE, Huang DCS and Strasser A. Bmf: A Proapoptotic BH3-Only Protein Regulated by Interaction with the Myosin V Actin Motor Complex, Activated by Anoikis Science, 2001; 293: 1829-1832.
64. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T and Tanaka N. Noxa, a BH3-Only Member of the Bcl-2 Family and Candidate Mediator of p53-Induced Apoptosis Science, 2000; 288: 1053-1058.
65. Han J, Flemington C, Houghton AB, Gu Z, Zambetti GP, Lutz RJ, Zhu L and Chittenden T. Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals Proc. Natl. Acad. Sci. USA, 2001; 98:11318–11323.
66. Nakano K and Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell. 2001; 7(3): 683-694.
67. Yu J, Zhang L, Hwang PM, Kinzler KW and Vogelstein B. PUMA induces the rapid apoptosis of colorectal cancer cells. J Yu, L Zhang, PM Hwang, KW Kinzler, and B Vogelstein. Mol Cell. 2001; 7(3): 673-682.
68. Villunger A, Michalak E, Coultas L, Müllauer F, B?ck G, Ausserlechner MJ, Adams JM and Strasser A. p53- and Drug-Induced Apoptotic Responses Mediated by BH3-Only Proteins Puma and Noxa. Science. 2003; 302: 1036.
69. Hsu Y-T and Youle RJ. Bax in Murine Thymus Is a Soluble Monomeric Protein That Displays Differential Detergent-induced Conformations J. Biol. Chem. 1998; 273: 10777-10783.
70. Griffiths GJ, Corfe BM, Savory P, Leech S, Esposti MD, Hickman JA and Dive C. Cellular damage signals promote sequential changes at the N-terminus and BH-1 domain of the pro-apoptotic protein Bak. Oncogene, 2001; 20(52): 7668-7676.
71. Antonsson B, Montessuit S, Sanchez B and Martinou JC. Bax Is Present as a High Molecular Weight Oligomer/Complex in the Mitochondrial Membrane of Apoptotic Cells. J. Biol. Chem. 2001; 276: 11615-11623.
72. Du C, Fang M, Li Y, Li L and Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000; 102(1): 33-42.
73. Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ and Vaux DL. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell. 2000; 102(1): 43-53.
74. Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K and Takahashi R. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP,inducing cell death. Mol Cell 2001; 8(3): 613-21.
75. Li LY, Luo X and Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 2001; 412(6842): 95-99.
76. Parrish J, Li L, Klotz K, Ledwich D, Wang X and Xue D. Nature, 412, 90–94. Mitochondrial endonuclease G is important for apoptosis in C. elegans. Nature 2001; 412(6842): 90-94.
77. Zong WX, Li C, Hatzuvassiliou G, Lindsten T, Yu QC, Yuan J and Thompson CB. Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis J. Cell Biol. 2003; 162: 59-69.
78. Susin SA, Zamzami N, Castedo M, Hxrsch T, Marchetti P, Macho A, Daugas E, Geuskens M, Kroemer G. Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J. Exp. Med. 1996; 184: 1331-1341.
79. Candé C, Cecconi F, Dessen P, Kroemer G. Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death? J Cell Sci. 2002; 115: 4727-4734.
80. Crescenzi E, Palumbo G and Brady HJ. Bcl-2 activates a programme of premature senescence in human carcinoma cells. Biochem J. 2003; 375(Pt 2): 263-74.
81. Borner C. Diminished Cell Proliferation Associated with the Death-protective Activity of Bcl-2 J. Biol. Chem. 1996; 271: 12695.
82. O’Reilly LA, Huang DCS and Strasser A. The cell death inhibitor Bcl-2 and its homologues influence control of cell cycle entry. EMBO J. 1996; 15(24): 6979-90.
83. Marvel J, Perkins GR, Lopez-Rivas A and Collins MKL. Growth factor starvation of bcl-2 overexpressing murine bone marrow cells induced refractoriness to IL-3 stimulation of proliferation. Oncogene. 1994 Apr;9(4):1117-1122.
84. Mazel S, Burtrum D and Petrie HT. Regulation of cell division cycle progression by bcl-2 expression: a potential mechanism for inhibition of programmed cell death J. Exp. Med. 1996; 183: 2219-2226.
85. Chattopadhyay A, Chiang CW, Yang E. BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest. Oncogene. 2001; 20(33): 4507-18.
86. Vairo G, Innes KM, Adams JM. Bcl-2 has a cell cycle inhibitory function separable from its enhancement of cell survival. Oncogene. 1996; 13(7): 1511-1519.
87. Furukawa Y, Iwase S, Kikuchi J, Terui Y, Nakamura M, Yamada H, Kano Y, Matsuda M. Phosphorylation of Bcl-2 protein by CDC2 kinase during G2/M phases and its role in cell cycle regulation. J. Biol. Chem. 2000; 275: 21661-7.
88. Scatena CD, Stewart ZA, Mays D, Tang LJ, Keefer CJ, Leach SD, Pietenpol JA. Mitotic phosphorylation of Bcl-2 during normal cell cycle progression and Taxol-induced growth arrest. J. Biol. Chem. 1998; 273: 30777-30784.
89. Facchini LM, Penn LZ. The molecular role of Myc in growth and transformation: recent discoveries lead to new insights. FASEB J. 1998; 12: 633-651.
90. Penn LJ, Laufer EM, Land H. C-MYC: evidence for multiple regulatory functions. Semin Cancer Biol. 1990; 1: 69-80.
91. Born TL, Frost JA, Schonthal A, Prendergast GC, Feramisco JR. c-Myc co-operates with activated Ras to induce the cdc2 promoter. Mol. Cell Biol. 1994; 14: 5710.
92. Kim YH, Buchholz. MA, Chrest FJ, Nordin AA. Up-regulation of c-myc induces the gene expression of the murine homologues of p34cdc2 and cyclin-dependent kinase-2 in T lymphocytes. J. Immunol. 1994; 152: 4328.
93. Beier R, Burgin A, Kiermaier A, Fero M, Karsunky H, Saffrich R, Moroy T, Ansorge W, Roberts J, Eilers M. Induction of cyclin E-cdk2 kinase activity, E2F-dependent transcription and cell growth by Myc are genetically separable events. EMBO J. 2000; 19; 5813.
94. Dang CV. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol. Cell Biol. 1999; 19:1.
95. Grandori C, Cowley SM, James LP, Eisenman RN. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu. Rev. Cell Dev. Biol. 2000; 16:653.
96. Conzen SD, Gottlob K, Kandel ES, Khanduri P, Wagner AJ, O?Leary M, Hay N. Induction of cell cycle progression and acceleration of apoptosis are two separablefunctions of c-Myc: transrepression correlates with acceleration of apoptosis. Mol Cell Biol. 2000; 20: 6008.
97. Thompson EB. The many roles of c-Myc in apoptosis. Annu Rev Physiol. 1998; 60: 575.
98. Hermeking H, Eick D. Mediation of c-Myc-induced apoptosis by p53. Science 1994; 265: 2091.
99. Hsu B, Marin MC, el Naggar AK, Stephens LC, Brisbay S, McDonnell TJ. Evidence that c-myc mediated apoptosis does not require wild-type p53 during lymphomagenesis. Oncogene 1995; 11: 175.
100.Wang R, Brunner T, Zhang L, Shi Y. Fungal metabolite FR901228 inhibits c-Myc and Fas ligand expression. Oncogene 1998; 17: 1503.
101.Reynolds JE, Yang T, Qian L, Jenkinson JD, Zhou P, Eastman A, Craig RW. Mcl-1, a member of the Bcl-2 family, delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells. Cancer Res. 1994; 54: 6348.
102.Hipfner DR, Cohen SM. Connecting proliferation and apoptosis in development and disease. Nat Rev Mol Cell Biol. 2004; 5: 805-815.
103.Senderowicz AM. Cyclin-dependent kinases as new targets for the prevention and treatment of cancer. Hematol Oncol Clin North Am 2002; 16:1229.
1. 郁仁存主编,中医肿瘤学(上册)。北京:科学出版社,1983。
2. 曾益新主编,肿瘤学。北京:人民卫生出版社,1999。
3. Devita VT et al. Cancer: Principles & Practice of Oncology, 7th ed. 2005.
4. Marchall EK Jr. Historical perspectives in chemotherapy. Adv Chemother, 1964; 13: 1-8.
5. Farber S, Diamond LK, Mercer RD, Sylverster RF, Wolff JA. Temperory remission in acute leukemia in children produced by folic acid antagonist
4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med 1948; 238: 787.
6. Haskell CM. Cancer Treatment, 5th edition. Philadelphia, PA: W.B. Saunders Com. 2001;p 63.
7. Boyd MR. Status of the NCI preclinical antitumor drug discovery screen. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology Updates, vol. 3, no. 10. Philadelphia: Lippincott. 1989: 1-12.
8. Skipper HE, Schabel FM, Wilcox WS. Experimental evaluation of potential anti-cancer agents. XII. On the criteria and kinetics associated with “curability” of experimental leukemia. Cancer Chemother Rep 1964; 35: 1.
9. Skehan P, Storeng R, Scudiero D et al. New colorimetric cytotoxity assay for anticancer drug screening. JNCI 1990; 82:1107.
10. Murry A, Hunt T. The cell cycle: an introduction. New York: W. H. Freeman, 1993; p1.
11. Jessani N, Niessen S, Mueller BM, Cravatt BF. Breast Cancer Cell Lines Grown in Vivo What Goes in Isn’t Always the Same as What Comes Out. Cell Cycle 2005; 4(2): 253-255.
12. Gong J, Bhatia U, Traganos F, Darzynkiewicz Z. Expression of cyclins A, D2 and D3 in individual normal mitogen stimulated lymphocytes and in MOLT-4 leukemic cells analyzed by multiparameter flow cytometry. Leukemia, 1995; 9:893-899.
13. Gong JP, Traganos F, Darzynkiewicz Z. Expression of cyclins B and E in individual MOLT-4 cells and in stimulated human lymphocytes during their progression through the cell cycle. Int J Oncol, 1993; 3: 1037-1042. 75
14. Appelt K, Baquet RJ, Bartlett CA, et al. Design of enzyme inhibitors using iterative protein crystallographic analysis. J Med Chem 1991; 3:1925.
15. Rowinsky EK, Donehower RC. Drug therapy: paclitaxel (Taxol). N Engl J Med 1995; 332:1004.
16. Abal M, Andreu JM, Barasoain I. Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Cancer Drug Targets 2003; 3:193.
17. Mann J. Steps to a successful synthesis. Nature 1994; 367:594.
18. Gordon M. Taxol supply problem? What problem? Nat Biotechnol 1996; 14:1635.
19. Wartmann M, Altmann KH. The biology and medicinal chemistry of epothilones. Curr Med Chem Anti-Canc Agents 2002; 2:123.
20. Rothermal J, Wartmann M, Chen T et al. EPO906 (epothilone B): a promising novel microtubule stabilizer. Semin Oncol 2003; 30[Suppl 6]: 51.
21. Garcia-Carbonero R, Supko JG. Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. Clin Cancer Res 2002; 8:641.
22. Pizxzolato JF, Saltz LB. The camptothecins. Lancet 2003; 361:2235.
23. Meng LH, Liao ZY, Pommier Y. Non-camptothecin DNA topoisomerase I inhibitors in cancer therapy. Curr Top Med Chem 2003; 3:305.
24. Sawyers C. Targeted cancer therapy. Nature 2004; 432: 294-297.
25. Senderowicz AM. Cyclin-dependent kinases as new targets for the prevention and treatment of cancer. Hematol Oncol Clin North Am 2002; 16:1229.
26. Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. Cancer 2002; 94:1593.
27. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the ABL tyrosine kinase on the growth of BCR-ABL positive cells. Nat Med 1996; 2:561.
28. Demetri GD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors N Engl J Med 2002; 347:472.
2. Debatin KM. Activation of apoptosis pathways by anticancer drugs. Adv Exp Med Biol. 1999; 457:237-244.
3. Marchall EK Jr. Historical perspectives in chemotherapy. Adv Chemother, 1964; 13:1-8.
4. Robert C et al. Cancer Medicine, 5th ed. 2000.
5. Charles M. Haskell, Cancer Treatment, 5th ed. 2001.
6. Derek Crowther, Cancer Chemotherapy, in Treatment of Cancer, Chapter 17:p74, Keith E. Halnan eds, London, 1982.
7. Hartwell LH and Kastan KB. Cell cycle control and cancer. Science, 1994; 266:1821-1828.
8. Hunter T and Pines J. Cyclins and cancers. Cell, 1991; 66:1071-1074.
9. Annie Borgne and Roy M. Golsteyn, The Role of Cyclin-Dependent Kinase in Apoptosis, in Progress in Cell cycle Research, Vol. 5, chapter 46:p453-459, Meijer L., Jezequel A., and Roberge M. eds, 2003.
10. J Gong, U Bhatia, F Traganos and Z Darzynkiewicz, Expression of cyclins A, D2 and D3 in individual normal mitogen stimulated lymphocytes and in MOLT-4 leukemic cells analyzed by multiparameter flow cytometry. Leukemia, 1995; 9:893-899.
11. JP Gong, F Traganos and Z Darzynkiewicz, Expression of cyclins B and E in individual MOLT-4 cells and in stimulated human lymphocytes during their progression through the cell cycle. Int J Oncol, 1993; 3: 1037-1042.
12. JP Gong, F Traganos and Z Darzynkiewicz, Growth Imbalance and altered expression of cyclins B1, A, E, and D3 in MOLT-4 cells synchronized in the cell cycle by Inhibitors of DNA replication. Cel Grow & Diff, 1995; 6:1485-1493.
13. 吴剑宏,细胞周期调控细胞凋亡的研究,华中科技大学同济医学院博士学位论文,2003。
14. 冯永东,细胞凋亡与细胞周期的协同及分子机制研究,华中科技大学同济医学院博士学位论文,2004。
15. 谢大兴,人类在体增殖细胞的细胞周期调控机制,华中科技大学同济医学院博士学位论文,2005。
1. Debatin KM. Activation of apoptosis pathways by anticancer drugs. Adv Exp Med Biol. 1999; 457:237-244.
2. Boyd MR. Status of the NCI preclinical antitumor drug discovery screen. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology Updates, vol. 3, no. 10. Philadelphia: Lippincott. 1989:1-12.
3. Skipper HE, Schabel FM Jr, Wilcox WS. Experimental evaluation of potential anticancer agents. XXI. Scheduling of arabinosylcytosine to take advantage of its S-phase specificity against leukemia cells. Cancer Chemother Rep 1967; 51:125-165.
4. Li LH, Olin EJ, Fraser TJ, Bhuyan BK. Phase specificity of 5-Azacytidine against mammalian cells in tissue culture. Cancer Res 1970; 30:2770-2775.
5. Li LH, Fraser TJ, Olin EJ, Bhuyan BK. Action of camptothecin on mammalian cells in culture. Cancer Res 1972; 32:2643-2650.
6. Hennequin C, Giocanti N, Favaudon V. S-phase specificity of cell killing by docetaxel (Taxotere) in synchronized HeLa cells. Br J Cancer 1995; 71:1194-1198.
7. Stephen EM, Hidemi S, Klaus GB. Vinblastine and griseofulvin reversibly disrupt the living mitotic spindle. Science 1968; 160:770-771.
8. Tao D, Wu J, Feng Y, Qin J, Hu J, Gong J. New method for the analysis of cell cycle-specific apoptosis. Cytometry. 2004; 57A(2): 70-74.
9. Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, Green DR. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med 1995; 182: 1545-1556.
10. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972; 26(4): 239-257.
11. Arends MJ, Morris RG, Wyllie AH. Apoptosis. The role of the endonuclease. Am J Pathol. 1990; 136(3): 593-608.
12. Gong J, Traganos F, Darzynkiewicz Z. A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry. Anal Biochem. 1994; 218(2): 314-319.
13. Olive PL, Banath JP, Durand RE. Heterogeneity in radiation-induced DNA damage and repair in tumor and normal cells measured using the "comet" assay. Radiat Res. 1990; 122(1): 86-94.
14. Gorczyca W, Gong J, Darzynkiewicz Z. Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assays. Cancer Res. 1993; 53:1945-1951.
15. Smolewski P, Grabarek J, Halicka HD, Darzynkiewicz Z. Assay of caspase activation in situ combined with probing plasma membrane integrity to detect three distinct stages of apoptosis. J Immunol Methods. 2002; 265: 111-121.
16. Castedo M, Hirsch T, Susin SA, Zamzami N, Marchetti P, Macho A, Kroemer G. Sequential acquisition of mitochondrial and plasma membrane alterations during early lymphocyte apoptosis. J Immunol 1996; 157(2): 512-521.
17. Donehower RC, Karp JE, Burke PJ. Pharmacology and toxicity of high-dose cytarabine by 72-hour continous infusion. Cancer Treat Rep 1986; 70(9): 1059-1065.
18. Capizzi RL, White JC, Powell BL, Perrino F. Effect of dose on the pharmacokinetic and pharmacodynamic effects of cytarabine. Seminars Hematol 1991; 28(Suppl 4): 54-69.
19. Vincent T Devita et al. Cancer: Principles & Practice of Oncology, 6th ed. Philadelphia: Lippincott. 2001.
20. Huizing MT, Keung ACF, Rosing H, et al. Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol 1993; 11(11): 2127-2135.
21. Gianni L, Kearns CM, Giani A, Capri G, Vigano L, Lacatelli A, Bonadonna G, Egorin MJ. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetics/pharmacodynamic relationships in humans. J Clin Oncol 1995; 13(1): 180-190.
22. Rowinsky EK, Donehower RC. The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics. Pharmacol Ther 1991; 52(1): 35-84.
1. 岳东方,1901-2004 年诺贝尔奖得主及其所属单位,生命科学,2004;16(6):421-430。
2. David R. Hipfner and Stephen M. Cohen. Connecting proliferation and apoptosis in development and disease. Nature Rev Mol Cel Bio 2004; 5: 805-815.
3. Annie B and Roy MG, The Role of Cyclin-Dependent Kinase in Apoptosis, in Progress in Cell cycle Research, Vol. 5, chapter 46:p453-459, Meijer L., Jezequel A., and Roberge M. eds, 2003.
4. J Gong, U Bhatia, F Traganos and Z Darzynkiewicz, Expression of cyclins A, D2 and D3 in individual normal mitogen stimulated lymphocytes and in MOLT-4 leukemic cells analyzed by multiparameter flow cytometry. Leukemia, 1995; 9:893-899.
5. JP Gong, F Traganos and Z Darzynkiewicz, Expression of cyclins B and E in individual MOLT-4 cells and in stimulated human lymphocytes during their progression through the cell cycle. Int J Oncol, 1993; 3: 1037-1042.
6. JP Gong, F Traganos and Z Darzynkiewicz, Growth Imbalance and altered expression of cyclins B1, A, E, and D3 in MOLT-4 cells synchronized in the cell cycle by Inhibitors of DNA replication. Cel Grow & Diff, 1995; 6:1485-1493.
7. 谢大兴,人类在体增殖细胞的细胞周期调控机制,华中科技大学同济医学院博士学位论文,2005。
8. Dustin P. The centennial of the discovery of the antimitotic properties of colchicines. Rev Med Brux. 1989; 10(9): 385-90.
9. T. J. Mitchison and E. D. Salmon. Mitosis: a history of division. Nature Cel Biol 2001; 3:17-21.
10. Boyd MR. Status of the NCI preclinical antitumor drug discovery screen. PPO Updates, 1989; 8:1.
11. Skipper HE, Schabel FM, Wilcox WS. Experimental evaluation of potential anti-cancer agents. XII. On the criteria and kinetics associated with “curability” of experimental leukemia. Cancer Chemother Rep 1964; 35:1.
12. Brown JM, Wouters BG. Does apoptosis contribute to tumer cell sensitivity toanticancer agents? In Cancer Drug Discovery and Development Series: Apoptosis and Cancer Chemotherapy, chapter 1:p12-13, John AH and Caroline D eds, 1999.
13. Nadim Jessani, Sherry Niessen, Barbara M. Mueller, Benjamin F. Cravatt. Breast Cancer Cell Lines Grown in Vivo What Goes in Isn’t Always the Same as What Comes Out. Cell Cycle 2005; 4(2): 253-255.
14. Bin-Bing S. Zhou, Stephen J. Elledge. The DNA damage response: putting checkpoints in perspective. Nature, 2000; 408(23): 433-439.
15. Iliakis G, Ya W, Jun G and Huichen W. DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene, 2003; 22: 5834-5847.
16. J Bartek, C Lukas and J Lukas. Checking on DNA damage in S phase. Nature Rev Mol Cel Bio 2004; 5: 792-804.
17. 吴剑宏,细胞周期调控细胞凋亡的研究,华中科技大学同济医学院博士学位论文,2003。
18. 冯永东,细胞凋亡与细胞周期的协同及分子机制研究,华中科技大学同济医学院博士学位论文,2004。
19. Lisa AP, Gurmit S and Jonathan ML. Abundance of cyclin B1 regulates g-radiation-induced apoptosis. Blood. 2000; 95: 2645-2650.
20. Bin-Bing Z, Hong LL, Jun YY and Marc WK. Caspase-dependent activation of cyclin-dependent kinases during Fas-induced apoptosis in Jurkat cells. PNAS 1998; 95: 6785–6790.
21. L. Shi, W.K. Niskioka, J. Th'ng, E.M. Bradbury, D.W. Litchfield, A.H. Greenberg, Premature p34cdc2 activation required for apoptosis, Nature 1994; 263: 1143-1145.
22. L. Shi, G. Chen, D. He, D.G. Bosc, D.W. Litchfield, A.H. Greenberg, Granzyme B induces apoptosis and cyclin A-associated cyclin-dependent kinase activity in all stages of the cell cycle, J. Immunol. 157 (1996) 2381-2385.
23. Hiromura K, Pippin JW, Blonski MJ, Roberts JM, Shankland SJ. The subcellular localization of cyclin dependent kinase 2 determines the fate of mesangial cells: role in apoptosis and proliferation. Oncogene 2002; 21: 1750-1758.
24. K Hiromural, JW Pippin, MJ Blonskil, JM Roberts and SJ Shankland. Thesubcellular localization of cyclin dependent kinase 2 determines the fate of mesangial cells role in apoptosis and proliferation. Oncogene 2002; 21: 1750-1758.
25. Anne Hakem, Takehiko Sasaki, Ivona Kozieradzki, and Josef M. Penninger The Cyclin-dependent Kinase Cdk2 Regulates Thymocyte Apoptosis. J. Exp. Med.
26. Katrien Vermeulen, Zwi N. Berneman and Dirk R. Van Bockstaele. Cell cycle and apoptosis. Cell Prolif. 2003; 36:165–175.
27. Abrams JM, White MA. Coordination of cell death and the cell cycle: linking proliferation to death through private and communal couplers. Cur Opin Cel Bio 2004; 16:634–638.
28. Halicka HD, Seiter K, Feldman EJ, Traganos F, Mittelman A, Ahmed T, Darzynkiewicz Z. Cell cycle specificity of apoptosis during treatment of leukaemias. Apoptosis 1997; 2: 25-39.
1.现代肿瘤治疗药物学,廖子君等主编。-西安:世界图书出版西安公司,2002.2.
2.Handbook of Cancer Chemotherapy (5th edition), Roland T. Skeel, 1999. -p8
3.Cancer Treatment (5th edition), Charles M. Haskell, 2001. -p104
4.Clinical Oncology (2nd edition), Abeloff MD, 1999.
5.血液肿瘤学,沈志祥等主编,-北京:人民卫生出版社,1999.-p57
1. Kerr JFR, Wyllie AH, Curie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239-257.
2. 岳东方,1901-2004 年诺贝尔奖得主及其所属单位,生命科学,2004;16(6):421-430。
3. Guimaraes C A, Linden R. Programmed cell death Apoptosis and alternative deathstyles. Eur J Biochem. 2004; 271:1638-1650.
4. Degterev A, Huang Z, Boyce M et al. Chemical inhibitor of nonapoptotic death with therapeutic potential for ischemic brain injury. Nat Chem Biol 2005; 1(2): 112-119.
5. Fiers W, Beyaert R, Declercq W, Vandenabeele P. More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene 1999; 18: 7719-7730.
6. Zeiss CJ. The Apoptosis-Necrosis Continuum: Insights from Genetically Altered Mice. Vet Pathol 2003; 40:481-495.
7. 兰蕾,赫荣乔。细胞周期分子机制的成功探索-2001 年诺贝尔生理及医学奖部分工作介绍。生物化学与生物物理进展,2001; 28: 773-777。
8. Qin JC, Tao DD, Duan R, Leng Y, Shen ML, Zhou H, Feng YD, Gao C,Yu Y, Li QD, Hu JB, Gong JP. Cytokinetic analysis of cell cycle and sub-phases in MOLT-4 cells by cyclin E + A/DNA multiparameter flow cytometry. Oncol Rep 2002; 9: 1041-1045.
9. Borgne A, Golsteyn RM. The role of cyclin-dependent kinases in apoptosis. In: Meijer L, Jezequel A, Roberge M, ed. Progress in Cell Cycle Research, 2003; 5: 453-459.
10. Hipfner DR, Cohen SM. Connecting proliferation and apoptosis in development and disease. Nat Rew Mol Cell Biol 2004; 5: 805-815.
11. Alenzi FQB. Links between apoptosis, proliferation and the cell cycle. Br J Biomed Sci 2004; 61(2): 99-102.
12. Nahle Z, Polakoff J, Davuluri RV, McCurrach ME, Jacobson MD, Narita M, Zhang MQ, Lazebnik Y, Bar-Sagi D, Lowe SW. Direct coupling of the cell cycle and cell death machinery by E2F. Nat Cell Biol 2002; 4:859-864.
13. Gil-Gomez G, Berns A, Brady HJM. A link between cell cycle and cell death Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis. EMBO J 1998; 17(24): 7209-7218.
14. Vermeulen K, Berneman ZN, Van Bockstaele DR. Cell cycle and apoptosis. Cell Prolif, 2003,36:165-175.
15. Chapter 18. Cell-Cycle Control and apoptosis. In: Alberts B, Johnson A, Lewis J et al. ed. Essential Cell Biology, 2nd edition. New York: Garland Science/Taylor & Francis Group, 2003; 612-636.
16. Pardee AB. G1 events and regulation of cell proliferation. Science 1989; 246:603-608.
17. 龚建平,第六章 细胞周期与肿瘤。曾益新主编,肿瘤学,北京:人民卫生出版社,1999。
18. Iliakis G, Ya W, Jun G and Huichen W. DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene, 2003; 22: 5834-5847.
19. Degterev A, Boyce M, Yuan J. A decade of caspases. Oncogene 2003; 22: 8543-8567.
20. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis - the p53 network. Journal of Cell Science, 2003; 116: 4077-4085.
21. Nagata S. Apoptosis by death factor. Cell 1997; 88: 355-365.
22. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli K, Debatin K-M, Krammer PH, Peter ME. Two CD95 (APO-1 Fas) signaling pathways. The EMBO Journal, 1998; 17(6): 1675-1687.
23. Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 2003; 22: 8608-8618.
24. Kawahara A, Ohsawa Y, Matsumura H, Uchiyama Y, Nagata S. Caspase-independent cell killing by Fas-associated protein with death domain. Journal of Cell Biology 1998; 143:1353-1360.
25. Kitanaka C, Kuchino Y. Caspase-independent programmed cell death with necrotic morphology. Cell Death and Differentiation 1993; 6: 508-515.
26. Green DR. Apoptotic pathways: ten minutes to death. Cell 2005; 121: 671-674.
27. Green DR, Amarante-Mendes GP. The point of no return. Results Probl Cell Differ. 1998; 24: 45-61.
28. Shi L, Niskioka WK, Th'ng J, Bradbury EM, Litchfield DW, Greenberg AH. Premature p34cdc2 activation required for apoptosis. Nature 1994; 263: 1143-1145.
29. Bin-Bing Z, Hong LL, Jun YY and Marc WK. Caspase-dependent activation of cyclin-dependent kinases during Fas-induced apoptosis in Jurkat cells. PNAS 1998; 95: 6785–6790.
30. Harvey KJ, Lukovic D, Ucker DS. Caspase-dependent Cdk activity is a requisite effector of apoptotic death events. J Cell Biol. 2000; 148: 59-72.
31. Meikrantz W, Schlegel R. Suppression of apoptosis by dominant negative mutants of cyclin-dependent protein kinases, J. Biol. Chem. 21996; 71: 10205-10209.
32. Sandal T, C Stapnes, Kleivdal H, Hedin L, Doskeland SO. A novel, extraneuronal role for cyclin-dependent protein kinase (CDK5). Modulation of cAMP-inducedapoptosis in rat leukemia cells. J. Biol. Chem. 2002; 277: 20783-20793.
33. Kim SG, Kim SN, Jong HS, Kim NK, Hong SH, Kim SJ, Bang YJ. Caspase-mediated Cdk2 activation is a critical step to execute transforming growth factor-beta1-induced apoptosis in human gastric cancer cells. Oncogene 2001; 20: 1254-1265.
34. Hsu S, Yin S, Liu M, Reichert U, Ho WL. Involvement of cyclin-dependent kinase activities in CD437-induced apoptosis. Exp Cell Res 1999; 252: 332-341.
35. L. Shi, G. Chen, D. He, D.G. Bosc, D.W. Litchfield, A.H. Greenberg, Granzyme B induces apoptosis and cyclin A-associated cyclin-dependent kinase activity in all stages of the cell cycle, J. Immunol. 1996; 157: 2381-2385.
36. Gil-Gomez G, Berns A, Brady HJM. A link between cell cycle and cell death: Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis. The EMBO Journal. 1998; 17(24): 7209-7218.
37. Shen M, Feng Y, Gao C, Tao D, Hu J, Reed E, Li Q, Gong J. Detection of Cyclin B1 Expression in G1-Phase Cancer Cell Lines and Cancer Tissues by Postsorting Western Blot Analysis. Cancer Res 2004; 64: 1607–1610.
38. 冯永东,细胞凋亡与细胞周期的协同及分子机制研究,华中科技大学同济医学院博士学位论文,2004。
39. Shimizu T, O'Connor PM, Kohn K, Pommier Y. Unscheduled activation of cyclinB1/cdc2 kinase in human promyelocytic leukemia cell line HL60 cells undergoing apoptosis induced by DNA damage, Cancer Res. 1995; 55: 228-231.
40. Hahntow IN, Schneller F, Oelsner M, Weick K, Ringshausen I, Fend F, Peschel C, Decker T. Cyclin-dependent kinase inhibitor roscovitine induces apoptosis in chronic lymphocytic leukemia cells. Leukemia 2004; 18: 747-755.
41. Lane ME, Yu B, Lipson KE, Liang C, Sun L, Tang C, McMahon G, Pestell RG, Wadler S. A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells. Cancer Res. 2001; 61: 6170-6177.
42. Park DS, Farinelli SE, Greene LA. Inhibitors of cyclin-dependent kinases promote survival of post-mitotic neuronally differentiated PC12 cells and sympathetic neurons. J Biol Chem 1996; 271: 8161-8169.
43. Konishi Y, Lehtinen M, Donovan N, Bonni A. Cdc2 phosphorylation of Bad links the cell cycle to the cell death machinery. Mol Cell 2002; 9: 1005-1016.
44. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X (L). Cell 1996; 87: 619-628.
45. Hollstein M, Sidransky D, Vogelstein B, Hanis CC. p53 mutations in human cancers. Science 1991; 253:49-53.
46. Mutoh M, Lung FDT, Long YQ, Roller PP, Sikorski RS, O'Connor PM. A p21Waf1/Cip1 carboxyl-terminal peptide exhibited cyclin-dependent kinase inhibitory activity and cytotoxicity when introduced into human cells. Cancer Res. 1999; 59: 3480-3488.
47. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995; 81(3): 323-30.
48. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997; 88: 323-331.
49. Bunz F, Dutriaux H, Lengauer C, Waldman T, Zhou S, Brown J P, Sedivy JM, Kinzler KW, Vogelstein B. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science. 1998; 282: 1497-1501.
50. Ford JM. Regulation of DNA damage recognition and nucleotide excision repair: another role for p53. Mutation Research. 2005; 577: 195-202.
51. Fridman JS, Lowe SW. Control of apoptosis by p53. Oncogene. 2003; 22: 9030-9040.
52. Tao W, Levine AJ. Nucleocytoplasmic shuttling of oncoprotein Mdm2 is required for Mdm2-mediated degradation of p53. Proc Natl Acad Sci USA 1999; 96: 3077-3080.
53. Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature 1997; 387: 299-303.
54. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature 1997; 387: 296-299.
55. Fuchs SY, Adler V, Buschmann T, Wu X, Ronai Z. Mdm2 association with p53targets its ubiquitination. Oncogene 1998; 17: 2543-2547.
56. Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev 1993; 7: 1126-1132.
57. Cory S, Huang DCS, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003; 22: 8590-8607.
58. Bouillet P, Purton JF, Godfrey DI, Zhang L-C, Coultas L, Puthalakath H, Pellegrini M, Cory S, Adams JM and Strasser A. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature, 2002; 415(6874): 922-926.
59. Hildeman DA, Zhu Y, Mitchell TC, Bouillet P, Strasser A, Kappler J and Marrack P. Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. Immunity, 2002; 16(6): 759-767.
60. Bouillet P, Metcalf D, Huang DCS, Tarlinton DM, Kay TWH, Frank K?ntgen F, Adams JM and Strasser A. Proapoptotic Bcl-2 Relative Bim Required for Certain Apoptotic Responses, Leukocyte Homeostasis, and to Preclude Autoimmunity. Science. 1999; 286: 1735–1738.
61. Danial NN, Gramm CF, Scorrano L, Zhang CY, Krauss S, Ranger AM, Datta SR, Greenberg ME, Licklider LJ, Lowell BB, Gygi SP and Korsmeyer SJ. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature. 2003; 424(6951): 952-956.
62. Ranger AM, Zha J, Harada H, Datta SR, Danial NN, Gilmore AP, Kutok JL, Le Beau MM, Greenberg ME and Korsmeyer SJ. Bad-deficient mice develop diffuse large B cell lymphoma. Proc. Natl. Acad. Sci. USA, 2003; 100: 9324–9329.
63. Puthalakath H, Villunger A, O’Reilly LA, Beaumont JG, Coultas L, Cheney RE, Huang DCS and Strasser A. Bmf: A Proapoptotic BH3-Only Protein Regulated by Interaction with the Myosin V Actin Motor Complex, Activated by Anoikis Science, 2001; 293: 1829-1832.
64. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T and Tanaka N. Noxa, a BH3-Only Member of the Bcl-2 Family and Candidate Mediator of p53-Induced Apoptosis Science, 2000; 288: 1053-1058.
65. Han J, Flemington C, Houghton AB, Gu Z, Zambetti GP, Lutz RJ, Zhu L and Chittenden T. Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals Proc. Natl. Acad. Sci. USA, 2001; 98:11318–11323.
66. Nakano K and Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell. 2001; 7(3): 683-694.
67. Yu J, Zhang L, Hwang PM, Kinzler KW and Vogelstein B. PUMA induces the rapid apoptosis of colorectal cancer cells. J Yu, L Zhang, PM Hwang, KW Kinzler, and B Vogelstein. Mol Cell. 2001; 7(3): 673-682.
68. Villunger A, Michalak E, Coultas L, Müllauer F, B?ck G, Ausserlechner MJ, Adams JM and Strasser A. p53- and Drug-Induced Apoptotic Responses Mediated by BH3-Only Proteins Puma and Noxa. Science. 2003; 302: 1036.
69. Hsu Y-T and Youle RJ. Bax in Murine Thymus Is a Soluble Monomeric Protein That Displays Differential Detergent-induced Conformations J. Biol. Chem. 1998; 273: 10777-10783.
70. Griffiths GJ, Corfe BM, Savory P, Leech S, Esposti MD, Hickman JA and Dive C. Cellular damage signals promote sequential changes at the N-terminus and BH-1 domain of the pro-apoptotic protein Bak. Oncogene, 2001; 20(52): 7668-7676.
71. Antonsson B, Montessuit S, Sanchez B and Martinou JC. Bax Is Present as a High Molecular Weight Oligomer/Complex in the Mitochondrial Membrane of Apoptotic Cells. J. Biol. Chem. 2001; 276: 11615-11623.
72. Du C, Fang M, Li Y, Li L and Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000; 102(1): 33-42.
73. Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ and Vaux DL. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell. 2000; 102(1): 43-53.
74. Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K and Takahashi R. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP,inducing cell death. Mol Cell 2001; 8(3): 613-21.
75. Li LY, Luo X and Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 2001; 412(6842): 95-99.
76. Parrish J, Li L, Klotz K, Ledwich D, Wang X and Xue D. Nature, 412, 90–94. Mitochondrial endonuclease G is important for apoptosis in C. elegans. Nature 2001; 412(6842): 90-94.
77. Zong WX, Li C, Hatzuvassiliou G, Lindsten T, Yu QC, Yuan J and Thompson CB. Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis J. Cell Biol. 2003; 162: 59-69.
78. Susin SA, Zamzami N, Castedo M, Hxrsch T, Marchetti P, Macho A, Daugas E, Geuskens M, Kroemer G. Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J. Exp. Med. 1996; 184: 1331-1341.
79. Candé C, Cecconi F, Dessen P, Kroemer G. Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death? J Cell Sci. 2002; 115: 4727-4734.
80. Crescenzi E, Palumbo G and Brady HJ. Bcl-2 activates a programme of premature senescence in human carcinoma cells. Biochem J. 2003; 375(Pt 2): 263-74.
81. Borner C. Diminished Cell Proliferation Associated with the Death-protective Activity of Bcl-2 J. Biol. Chem. 1996; 271: 12695.
82. O’Reilly LA, Huang DCS and Strasser A. The cell death inhibitor Bcl-2 and its homologues influence control of cell cycle entry. EMBO J. 1996; 15(24): 6979-90.
83. Marvel J, Perkins GR, Lopez-Rivas A and Collins MKL. Growth factor starvation of bcl-2 overexpressing murine bone marrow cells induced refractoriness to IL-3 stimulation of proliferation. Oncogene. 1994 Apr;9(4):1117-1122.
84. Mazel S, Burtrum D and Petrie HT. Regulation of cell division cycle progression by bcl-2 expression: a potential mechanism for inhibition of programmed cell death J. Exp. Med. 1996; 183: 2219-2226.
85. Chattopadhyay A, Chiang CW, Yang E. BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest. Oncogene. 2001; 20(33): 4507-18.
86. Vairo G, Innes KM, Adams JM. Bcl-2 has a cell cycle inhibitory function separable from its enhancement of cell survival. Oncogene. 1996; 13(7): 1511-1519.
87. Furukawa Y, Iwase S, Kikuchi J, Terui Y, Nakamura M, Yamada H, Kano Y, Matsuda M. Phosphorylation of Bcl-2 protein by CDC2 kinase during G2/M phases and its role in cell cycle regulation. J. Biol. Chem. 2000; 275: 21661-7.
88. Scatena CD, Stewart ZA, Mays D, Tang LJ, Keefer CJ, Leach SD, Pietenpol JA. Mitotic phosphorylation of Bcl-2 during normal cell cycle progression and Taxol-induced growth arrest. J. Biol. Chem. 1998; 273: 30777-30784.
89. Facchini LM, Penn LZ. The molecular role of Myc in growth and transformation: recent discoveries lead to new insights. FASEB J. 1998; 12: 633-651.
90. Penn LJ, Laufer EM, Land H. C-MYC: evidence for multiple regulatory functions. Semin Cancer Biol. 1990; 1: 69-80.
91. Born TL, Frost JA, Schonthal A, Prendergast GC, Feramisco JR. c-Myc co-operates with activated Ras to induce the cdc2 promoter. Mol. Cell Biol. 1994; 14: 5710.
92. Kim YH, Buchholz. MA, Chrest FJ, Nordin AA. Up-regulation of c-myc induces the gene expression of the murine homologues of p34cdc2 and cyclin-dependent kinase-2 in T lymphocytes. J. Immunol. 1994; 152: 4328.
93. Beier R, Burgin A, Kiermaier A, Fero M, Karsunky H, Saffrich R, Moroy T, Ansorge W, Roberts J, Eilers M. Induction of cyclin E-cdk2 kinase activity, E2F-dependent transcription and cell growth by Myc are genetically separable events. EMBO J. 2000; 19; 5813.
94. Dang CV. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol. Cell Biol. 1999; 19:1.
95. Grandori C, Cowley SM, James LP, Eisenman RN. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu. Rev. Cell Dev. Biol. 2000; 16:653.
96. Conzen SD, Gottlob K, Kandel ES, Khanduri P, Wagner AJ, O?Leary M, Hay N. Induction of cell cycle progression and acceleration of apoptosis are two separablefunctions of c-Myc: transrepression correlates with acceleration of apoptosis. Mol Cell Biol. 2000; 20: 6008.
97. Thompson EB. The many roles of c-Myc in apoptosis. Annu Rev Physiol. 1998; 60: 575.
98. Hermeking H, Eick D. Mediation of c-Myc-induced apoptosis by p53. Science 1994; 265: 2091.
99. Hsu B, Marin MC, el Naggar AK, Stephens LC, Brisbay S, McDonnell TJ. Evidence that c-myc mediated apoptosis does not require wild-type p53 during lymphomagenesis. Oncogene 1995; 11: 175.
100.Wang R, Brunner T, Zhang L, Shi Y. Fungal metabolite FR901228 inhibits c-Myc and Fas ligand expression. Oncogene 1998; 17: 1503.
101.Reynolds JE, Yang T, Qian L, Jenkinson JD, Zhou P, Eastman A, Craig RW. Mcl-1, a member of the Bcl-2 family, delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells. Cancer Res. 1994; 54: 6348.
102.Hipfner DR, Cohen SM. Connecting proliferation and apoptosis in development and disease. Nat Rev Mol Cell Biol. 2004; 5: 805-815.
103.Senderowicz AM. Cyclin-dependent kinases as new targets for the prevention and treatment of cancer. Hematol Oncol Clin North Am 2002; 16:1229.
1. 郁仁存主编,中医肿瘤学(上册)。北京:科学出版社,1983。
2. 曾益新主编,肿瘤学。北京:人民卫生出版社,1999。
3. Devita VT et al. Cancer: Principles & Practice of Oncology, 7th ed. 2005.
4. Marchall EK Jr. Historical perspectives in chemotherapy. Adv Chemother, 1964; 13: 1-8.
5. Farber S, Diamond LK, Mercer RD, Sylverster RF, Wolff JA. Temperory remission in acute leukemia in children produced by folic acid antagonist
4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med 1948; 238: 787.
6. Haskell CM. Cancer Treatment, 5th edition. Philadelphia, PA: W.B. Saunders Com. 2001;p 63.
7. Boyd MR. Status of the NCI preclinical antitumor drug discovery screen. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology Updates, vol. 3, no. 10. Philadelphia: Lippincott. 1989: 1-12.
8. Skipper HE, Schabel FM, Wilcox WS. Experimental evaluation of potential anti-cancer agents. XII. On the criteria and kinetics associated with “curability” of experimental leukemia. Cancer Chemother Rep 1964; 35: 1.
9. Skehan P, Storeng R, Scudiero D et al. New colorimetric cytotoxity assay for anticancer drug screening. JNCI 1990; 82:1107.
10. Murry A, Hunt T. The cell cycle: an introduction. New York: W. H. Freeman, 1993; p1.
11. Jessani N, Niessen S, Mueller BM, Cravatt BF. Breast Cancer Cell Lines Grown in Vivo What Goes in Isn’t Always the Same as What Comes Out. Cell Cycle 2005; 4(2): 253-255.
12. Gong J, Bhatia U, Traganos F, Darzynkiewicz Z. Expression of cyclins A, D2 and D3 in individual normal mitogen stimulated lymphocytes and in MOLT-4 leukemic cells analyzed by multiparameter flow cytometry. Leukemia, 1995; 9:893-899.
13. Gong JP, Traganos F, Darzynkiewicz Z. Expression of cyclins B and E in individual MOLT-4 cells and in stimulated human lymphocytes during their progression through the cell cycle. Int J Oncol, 1993; 3: 1037-1042. 75
14. Appelt K, Baquet RJ, Bartlett CA, et al. Design of enzyme inhibitors using iterative protein crystallographic analysis. J Med Chem 1991; 3:1925.
15. Rowinsky EK, Donehower RC. Drug therapy: paclitaxel (Taxol). N Engl J Med 1995; 332:1004.
16. Abal M, Andreu JM, Barasoain I. Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Cancer Drug Targets 2003; 3:193.
17. Mann J. Steps to a successful synthesis. Nature 1994; 367:594.
18. Gordon M. Taxol supply problem? What problem? Nat Biotechnol 1996; 14:1635.
19. Wartmann M, Altmann KH. The biology and medicinal chemistry of epothilones. Curr Med Chem Anti-Canc Agents 2002; 2:123.
20. Rothermal J, Wartmann M, Chen T et al. EPO906 (epothilone B): a promising novel microtubule stabilizer. Semin Oncol 2003; 30[Suppl 6]: 51.
21. Garcia-Carbonero R, Supko JG. Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. Clin Cancer Res 2002; 8:641.
22. Pizxzolato JF, Saltz LB. The camptothecins. Lancet 2003; 361:2235.
23. Meng LH, Liao ZY, Pommier Y. Non-camptothecin DNA topoisomerase I inhibitors in cancer therapy. Curr Top Med Chem 2003; 3:305.
24. Sawyers C. Targeted cancer therapy. Nature 2004; 432: 294-297.
25. Senderowicz AM. Cyclin-dependent kinases as new targets for the prevention and treatment of cancer. Hematol Oncol Clin North Am 2002; 16:1229.
26. Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. Cancer 2002; 94:1593.
27. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the ABL tyrosine kinase on the growth of BCR-ABL positive cells. Nat Med 1996; 2:561.
28. Demetri GD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors N Engl J Med 2002; 347:472.