TRAIL对卵巢癌细胞株SKOV-3，A2780，PA-1的作用
摘要
目的：
比较肿瘤坏死因子相关凋亡诱导配体(TRAIL／Apo-2L)及顺铂对三种不同p53状态的卵巢癌细胞株(SKOV-3、A2780及PA-1)的生长抑制及凋亡诱导效应，评价TRAIL在卵巢癌治疗中的应用价值，了解卵巢癌细胞p53状态与卵巢癌化疗敏感性之间的关系。
方法：
利用MTT法比较TRAIL在5个浓度下(25、50、100、200、400ng／ml)对SKOV-3、A2780及PA-1三种卵巢癌细胞株的生长抑制情况；比较TRAIL、DDP及TRAIL联合DDP作用于SKOV-3、A2780及PA-1三种卵巢癌细胞株时的生长抑制情况；利用流式细胞仪PI法测定TRAIL、DDP及TRAIL联合DDP作用于SKOV-3、A2780及PA-1三种卵巢癌细胞株时的细胞凋亡情况。利用方差分析对实验结果进行统计。
结果：
1．TRAIL作用于SKOV-3、A2780及PA-1三组细胞24小时后均表现出一定的生长抑制效果，TRAIL在25ng／ml-400ng／ml 5个浓度梯度对三种细胞的抑制率((?)±s，％)分别为(按浓度由小至大排列)：SKOV3：1.1±0.54，15.3±4.56，31.0±4.95，41.3±8.21，42.2+9.77；A2780：3.2±0.89，
Objectives:
We compared the cytotoxicity and apoptosis inducing ability of TRAIL and cisplatin in 3 ovarian carcinoma cell lines (SKOV-3, A2780 and PA-1) with different p53 status to evaluate the potential clinical usefulness of TRAIL in ovarian carcinoma chemotherapy and the importance of p53 in chemotherapy resistance. Methods:
The 24hs growth inhibition of 3 ovarian carcinoma cell lines in respond to different concentration level TRAIL(25、 50、 100、 200、 400ng/ml) was determined by MTT assay. We also compare the growth inhibition curves of 3 cell lines in respond to TRAIL200ng/ml, DDP10μM and combination of DDP /TRAL respectively. The apoptosis rates of 3 cell lines treated by TRAIL200ng/ml, DDP10μM and combination of DDP /TRAL respectively for 24hs was measured by flow cytometry. Comparisons among the values were performed using ANOVA. A value of P <0.05 was considered statistically significant. Results:
We observed the 3 cell lines treated by TRAIL for 24h at the
比较肿瘤坏死因子相关凋亡诱导配体(TRAIL／Apo-2L)及顺铂对三种不同p53状态的卵巢癌细胞株(SKOV-3、A2780及PA-1)的生长抑制及凋亡诱导效应，评价TRAIL在卵巢癌治疗中的应用价值，了解卵巢癌细胞p53状态与卵巢癌化疗敏感性之间的关系。
方法：
利用MTT法比较TRAIL在5个浓度下(25、50、100、200、400ng／ml)对SKOV-3、A2780及PA-1三种卵巢癌细胞株的生长抑制情况；比较TRAIL、DDP及TRAIL联合DDP作用于SKOV-3、A2780及PA-1三种卵巢癌细胞株时的生长抑制情况；利用流式细胞仪PI法测定TRAIL、DDP及TRAIL联合DDP作用于SKOV-3、A2780及PA-1三种卵巢癌细胞株时的细胞凋亡情况。利用方差分析对实验结果进行统计。
结果：
1．TRAIL作用于SKOV-3、A2780及PA-1三组细胞24小时后均表现出一定的生长抑制效果，TRAIL在25ng／ml-400ng／ml 5个浓度梯度对三种细胞的抑制率((?)±s，％)分别为(按浓度由小至大排列)：SKOV3：1.1±0.54，15.3±4.56，31.0±4.95，41.3±8.21，42.2+9.77；A2780：3.2±0.89，
Objectives:
We compared the cytotoxicity and apoptosis inducing ability of TRAIL and cisplatin in 3 ovarian carcinoma cell lines (SKOV-3, A2780 and PA-1) with different p53 status to evaluate the potential clinical usefulness of TRAIL in ovarian carcinoma chemotherapy and the importance of p53 in chemotherapy resistance. Methods:
The 24hs growth inhibition of 3 ovarian carcinoma cell lines in respond to different concentration level TRAIL(25、 50、 100、 200、 400ng/ml) was determined by MTT assay. We also compare the growth inhibition curves of 3 cell lines in respond to TRAIL200ng/ml, DDP10μM and combination of DDP /TRAL respectively. The apoptosis rates of 3 cell lines treated by TRAIL200ng/ml, DDP10μM and combination of DDP /TRAL respectively for 24hs was measured by flow cytometry. Comparisons among the values were performed using ANOVA. A value of P <0.05 was considered statistically significant. Results:
We observed the 3 cell lines treated by TRAIL for 24h at the
引文
1．连利娟，林巧稚妇科肿瘤学．[M]．第三版，北京：人民卫生出版社，2000：403-593．
2. Ambrosini G ,Adida C ,Altieri DC. A novel antiapoptsis gene ,survivin ,expressed in cancer and lmyphoma[J]. Nat Med,1997,3 (8) :917
3. Daniel SO ,J eft rey SS ,Colet te A ,et al. Control of apoptosis during angiogenesis by survivin expression in endothelial cells [J] . Am J Pat hol ,2000,156(2) :393.
4. Yaginuma, Y, Westphal, H. Abnormal structure and expression of p53 gene in human ovarian carcinoma cell lines. Cancer Res., 52:4196-4199, 1992
5. Safrit JT,Breech JS,Bonavida B.Sensitivity of drug-resistant human ovarian tumor cell lines to combined effects of tumor necrosis factors(TNF-α)and doxorubicin:failure of the combination to modulate the MDR phenotype.Gynecol Oncol, 1993 ;48(2):214
6. Pestell K. E., Medlow C. J., Titley J. C., Kelland L. R., Walton Mo I. Characterisation of the p53 status, BCL-2 expression and radiation and platinum drug sensitivity of a panel of human ovarian cancer cell lines. Int. J. Cancer, 77: 913-918, 1998.;
7. KM Henkels, JJ Turchi .Induction of apoptosis in cisplatin-sensitive and -resistant human ovarian cancer cell lines. Cancer Research, 1997: 57 (20) 4488-4492
8. Pestell K. E., Medlow C. J., Titley J. C., Kelland L. R., Walton M. I. Characterisation of the p53 status, BCL-2 expression and radiation and platinum drug sensitivity of a panel of human ovarian cancer cell lines. Int. J. Cancer, 77: 913-918, 1998.;
9. Wu G. S., El-Deity W. S. p53 and chemosensitivity. Nat. Med., 2: 255-256, 1996
10. Evan GL. A matter of life and cell death [J]. Science, 1998,281 (5381) : 131721312.
11．梁志清，卵巢癌化疗耐药机制研究进展中国实用妇科与产科杂志 2005年7月第21卷第7期，446-448
12. Lowe SW Cancer therapy and p53 [J].Curr Opin Oncol 1995. 7(6): 547 —553
13. Vogelstein, B., Lane, D. and Levine, A. J. (2000). Surfing the p53 network. Nature 408, 307-310.
14. OConnor PM,Jackman J ,Bae I ,et al. Characterization of the p53 tumor suppressor pathway in cell lines of the national cancer institute anticancer drug screen and correlations with the growth2inhibitory potency of 123 anticancer agents[J]. Cancer Res ,1997,57:4285-4300
15. Siddik ZH, Mims B, Lozano G, etal. Independent pathways of p53 induction by cisplatin and X-rays in a cisplatin-resistant ovarian tumor cell line. Cancer Res, 1998, 58 (4) : 698-703
16. Reles A, Wen WH, Schmider A. Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer. Clin Cancer Res, 2001, 7(10):2984-2997.
17. Sato S ,Kigawa J ,Minagawa Y,et al . Chemosensitivity and p532dependent apoptosis in epithelial ovarian carcinoma [J] . Cancer , 1999 , 86(7) :1307-1313.
18. Irie T ,Kigawa J ,Minagawa Y,et al . Alteration of a p53 gene status affects outcome of patients with recurrent ovarian cancer [J]. Oncology, 2000,58(3):237-241.
19. Ashkenazi, A. and Dixit, V. M. (1998). Death receptors: signaling and modulation. Science 281,1305-1308.
20. Newton, K. and Strasser, A. (2000) J. Exp. Med. 191,195- 200
21. Schuler, M., Bossy-Wetzel, E., Goldstein, J. C, Fitzgerald, P.and Green, D. R. (2000) J. Biol. Chem. 275, 7337-7342
22. Kuida, K., Haydar, T. F., Kuan, C.-Y., Gu, Y., Taya, C.,Karasuyama, H., Su, M. S. S., Rakic, P. and Flavell, R. A. (1998) Cell 94, 325-337
23. Hakem, R., Hakem, A., Duncan, G. S., Henderson, J. T.,Woo, M., Soengas, M. S., Elia, A., de al Pompa, J. L., Kagi, D., Khoo, W., et al. (1998) Cell 94, 339±352
24. Cecconi, F., Alvarez-Bolado, G., Meyer, B. I., Roth, K. A. and Gruss, P. (1998) Cell 94, 727-737.
25. Yoshida, H., Kong, Y.-Y., Yoshida, R., Elia, A. J., Hakem, A., Hakem, R., Penninger, J. M. and Mak, T. W. (1998) Cell 94, 739-750.
26. Soengas, M. S., Alarco! n, R. M., Yoshida, H., Giaccia, A. J., Hakem, R., Mak, T. W. and Lowe, S. W. (1999) Science 284, 156-159
27. Havell EA, Fiers W, North RJ. The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity. J Exp Med 1988; 167: 1067-1085.
28. Ogasawara J, Watanabe-Fukunaga R, Adachi M, et al. Lethal effect of the anti-Fas antibody in mice [erratum appears in Nature 1993;365:568]. Nature 1993; 364: 806-809
29. Kischkel FC, Lawwrence DA, Chuntharapai A, et al.Apo2L/TRAIL-dependent recruitment of endogenous FADD and Caspase-8 to death receptors 4 and 5.Immunity,2000,12(6):611-620
30. Shivapurkar N,Toyooka S, Toyooka KO, et al. Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types. Int J Cancer. 2004,109(5): 786 - 792
31.Miyashita T,Kawakami A, Nakashima T, et al. Osteoprotegerin(OPG) acts as an endogenous decoy receptor in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of fibroblastlike synovial cells. Clin Exp Immunol,2004,137(2):430-436
32. Gasparri, A. et al. Tumor pretargeting with avidin improves the therapeutic index of biotinylated tumor necrosis factor alpha in mouse models. Cancer Res. 59, 2917-2923 (1999).
33. Arap, W., Pasqualini, R. & Ruoslahti, E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279, 377-380 (1998).
34. Pasqualini, R., Koivunen, E. & Ruoslahti, E. Alpha v integrins as receptors for tumor targeting by circulating ligands. Nat. Biotechnol. 15, 542-546 (1997).
35. Siervo-Sassi RR. Marrangoni AM. Feng X. Naoumova N. Winans M. Edwards RP. Lokshin A. Physiological and molecular effects of Apo2L/TRAIL and cisplatin in ovarian carcinoma cell lines. [Journal Article] Cancer Letters. 190(1):61-72, 2003 Feb 10.
36. Wu XX ,Ogawa O ,Kakehi Y ,et al. TRAIL and chemotherapeutic drugs in cancer therapy [J] . Vitam Horm ,2004 ,67 (4) :365.
37. Sean K. Kelley, Louise A. Harris, David Xie, Laura DeForge, Klara Totpal, Jeanine Bussiere and Judith A. Fox, Preclinical Studies to Predict the Disposition of Apo2L/Tumor Necrosis Factor-Related Apoptosis-inducing Ligand in Humans: Characterization of in Vivo Efficacy, Pharmacokinetics, and Safety, 2001. 299(1), 31-38)
38. Andreas Evdokiou Stelios Bouralexis , Gerald J. Atkins , Chemotherapeutic agents sensitize osteogenic sarcoma cells, but not normal human bone cells, to apo21/trail-induced apoptosis .Cancer Cell Biology .2002 99(4) , 491 - 504.
39. (Eui-Cheol Shin1, Young Rim Seong2,Chul Hoon Kim3,et al Human hepatocellular carcinoma cells resist to TRAIL-induced apoptosis, and the resistance is abolished by cisplatin. EXPERIMENTAL and MOLECULAR MEDICINE, 2002. 34( 2), 114-122, )
40. Jo M, Kim TH, Seol DW, et al. Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med 2000;6:564-7
41. Walczak H, Miller RE, Ariail K, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo . Nat Med 1999;5: 157-63.
42. Denis Lane, Andre'anne Cartier, Sylvain L'Espe'rance, Marceline Co^te',Claudine Rancourt, and Alain Piche. Differential induction of apoptosis by tumor necrosis factor-relatedapoptosis-inducing ligand in human ovarian carcinoma cells, Gynecologic Oncology 93 (2004) 594-604, 594-604
43. Chuntharapai A, Dodge K, Grimmer K, et al. Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J Immunol 2001; 166: 4891-4898.
44. Human Genome Sciences Reports on Progress of Clinical Trials and Announces Goals for 2005 at JP Morgan Healthcare Conference. Accessed January 24,2005.
45. De Bono J, Attard G, Plummer R, et al. A phase I and pharmacokinetic (PK) study of an agonistic, fully human monoclonal antibody, HGSETR2, to the TNFalpha related apoptosis inducing ligand receptor 2 (TRAIL R2) in patients with advanced cancer [abstract]. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 61.
46. Hotte SJ, Oza AM, Le LH, et al. HGS-ETR1, a fully human monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand death receptor 1 (TRAILR1) in patients with advanced solid cancer: results of a phase I trial [abstract]. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 64.
47. Cohen RB, Meropol NJ, Padavic KM, et al. A phase I clinical trial of HGS-ETR1, an agonist monoclonal antibody to TRAILR1, in patients with advanced solid tumors. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 13.
48. Tolcher A. Translation targeting TRAIL receptors to the clinic. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 139-141.
1. Green DR. Apoptotie pathways: the roads to ruin [J] Cell.1 998; 94(6): 695—698
2. Soo-Jung P, Ching-Haung W, John DG, et al. Taxol Induces Caspase- 10-dependent Apoptosis. [J] Biol Chem, 2004; 279( 49): 51057- 51067
3. Merei H, Ine B, Tijdens, Gerard J. et al. Differential Regulation of Doxorubicin-induced Mitochondrial Dysfunction and Apoptosis by Bcl-2 in Mammary Adenocarcinoma. Cells, 2002; 277(27): 35869-35879
4. Kischkel FC, Lawwrence DA, Chuntharapai A, et al. Apo2L/RAIL- dependent recruitment of endogenous FADD and Caspase-8 to death receptors 4 and 5. Immunity, 2000; 12(6): 611-620
5. Shivapurkar N, Toyooka S, Toyooka KO, et al. Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types. Int J Cancer, 2004; 109(5): 786 - 792
6. Miyashita T, Kawakami A, Nakashima T, et al. Osteoprotegerin (OPG) acts as an endogenous decoy receptor in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis of fibroblastlike synovial cells. Clin Exp Immunol, 2004; 137(2): 430-436
7. Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat. Rev. Cancer, 2002; 2: 647-656.
8. Kuwana T., Mackey MR., Perkins G., et al. Bid, Bax and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell ,2002; 111:331-342.
9. Kelekar A, Thompson CB. Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol, 1998; 8: 324-330.
10. Yu J., Zhang L., Hwang P., et al. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol. Cell, 2001; 7: 673-682.
11. Bouillet P, Straser A. BH3-only proteins - evolutionarily conserved pro-apoptotic Bcl-2 family members essential for initiating programmed cell death. J. Cell Sci., 2002 ;115: 1567-1574.
12. Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell, 2001; 7: 683-694
13. Yu J, Wang Z., Kinzler K, et al. PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc. Natl. Acad. Sci. USA, 2003; 100: 1931-1936.
14. Kim TH, Zhao Y, Barber MJ, et al. Bid-induced cytochrome release is mediated by a pathway independent of mitochondrial permeability transition pore and Bax. J Biol Chem, 2000; 275: 39474
15. Oda E, Ohki R., Murasawa H., et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science, 2000; 288: 1053-1058.
16. Yoshide B, Kang YY, Yoshide R, et al. Apaf-1 is required for mitochondrial pathways of apoptosis and brain development [J].Cell, 1998; 94:739-750.
17. Adams JM, Cory S. Apoptosomes: engines for caspase activation. Curr. Opin. Cell Biol, 2002; 14: 715-720.
18. Daugas E, Susin SA, Zamzami N, et al. Mitochondria-nuclear translocation of AIF in apoptosis and necrosis[J]. FASEB, 2000, 14(5): 729-739.
19. Patterson S D, Spahr C S, Daudas E, et al. Mass spectrometric identification of proteins released from mitochondria undergoing permeability transition[J].Cell Death Differ, 2000, 7(2): 137-144.
20. Du C, Fang M, Li Y, et al. Smac a mitochondrial protein that promotes cytochrome C-dependent caspase activation by eliminating LAP inhibition[J].Cell,2000,102:33-42.
21. Verhagen A M, Ekert P. G.Identification of DLABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing LAP proteins[J]. Cell,2000,102(1):43-53.
22. Giaccia AJ, Kastan MB. The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev, 1998; 12: 2973-2983.
23. Vogt SR, Haupt Y. The cellular response to p53: the decision between life and death. Oncogene, 1999;18: 6145-6157.
24. Thornborrow E C, Patel S, Mastropietro AE, et al A conserved intronic response element mediates direct p53-dependent transcnptional activation of both the human and murine bax genes. Oncogene, 2002; 21: 990-999.
25. Marchenko ND, Zaika A, Moll UM. Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J. Biol. Chem, 2000; 275: 16202-16212
26. Mihara M, Erster S, Zaika A, et al. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell, 2003 ;11: 577-590.
27. Kannan, K., Kaminski, N., Rechavi, G., et al. DNA microarray analysis of genes involved mediated apoptosis: activation of Apaf-1. Oncogene 2001; 20, 3449-3455.
28. Moroni, M. C, Hickman, E. S., Denchi, E. L., et al. Apaf-1 is a transcnptional target for E2F and p53. Nat. Cell Biol. 2001; 3, 552-558
29. Robles, A. I, Bemmels, N. A., Foraker, A. B. et al. APAF-1 is a transcnptional target of p53 in DNA damage-induced apoptosis. Cancer Res. 2001; 61, 6660-6664.
30. Rozenfeld-Granot, G., Krishnamurthy, J., Kannan, K., et al. A positive feedback mechanism in the transcnptional activation of Apaf-1 by p53 and the coactivator Zac-1. Oncogene 2002; 21, 1469-1476.
31. Ding, H. F., McGill, G., Rowan, S., et al. Oncogene-dependent regulation of caspase activation by p53 protein in a cell-free system. J. Biol. Chem. 1998; 273, 28378-28383.
32. Varfolomeev, E. E., Schuchmann, M., Luria, V., Chiannilkulchai, N., Beckmann, J. S., Mett, I. L., Rebrikov, D., Brodianski, V. M., Kemper, O. C, Kollet, O. et al. (1998). Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo 1, and DR3 and is lethal prenatally. Immunity 9, 267-276.
33. MacLachlan, T. K. and El-Deiry, W. S. Apoptotic threshold is lowered by p53 transactivation of caspase-6. Proc. Natl. Acad. Sci. USA 2002; 99, 9492-9497.
34. Galande, S., Dickinson, L. A., Mian, I. S., et al. SATB1 cleavage by caspase 6 disrupts PDZ domainmediated dimerization, causing detachment from chromatin early in T-cell apoptosis. Mol. Cell. Biol. 2001; 21, 5591-5604.
35. Fuchs, E. J., McKenna, K. A. and Bedi, A. p53-dependent DNA damage-induced apoptosis requires Fas/APO-1-independent activation of CPP32beta. Cancer Res. 1997; 57, 2550-2554
36. O'Connor, L., Harris, A. W. and Strasser, A. CD95 (Fas/APO-1) and p53 signal apoptosis independently in diverse cell types. Cancer Res. 2000; 60,1217-1220.
37. Ghosh S, Karin M. Missing pieces in the NF-κB puzzle. Cell, 2002; 109(suppl): S81-S96
38. Chen C, Edelstein LC, Gelinas C. The Rel/ NF-κB family directly activates expression of the apotosis inhibitor Bcl-x. Mol Cell Biol, 2000; 20(8):2687-2695
39. Greten FR, Echmann L, Greten TF, et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell, 2004; 118(3):285-296
40. De Moissac D, Mustapha S, Greenberg AH, et al. Bcl-2 activates the transcription factor NFkappaB through the degradation of the cytoplasmic inhibitor IkappaBalpha.J Biol Chem. 1998 Sep 11; 273(37): 23946-51.
41. Li L, Liao J, Ruland J, et al. A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control.Proc Natl Acad Sci U S A. 2001 Feb 13;98(4): 1619-24
42. Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 2000; 19: 6680-6686.
43. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296: 1655-1657
44. Mayo, L. D. and Dormer, D. B. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem. Sci. 2002; 27, 462-467.
45. Testa, J. R. and Bellacosa, A. AKT plays a central role in tumorigenesis. Proc. Natl. Acad. Sci. USA 2001; 98,10983-10985.
46. Tolcher AW. Regulators of apoptosis as anticancer targets. Hematol Oncol Clin North Am 2002; 16: 1255-1267.
47. Ferreira CG, Epping M, Kruyt FA, et al. Apoptosis: target of cancer therapy. Clin Cancer Res 2002; 8: 2024-2034.
48. Havell EA, Fiers W, North RJ. The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity. J Exp Med 1988; 167: 1067-1085.
49. Ogasawara J, Watanabe-Fukunaga R, Adachi M, et al. Lethal effect of the anti-Fas antibody in mice. Nature 1993; 364: 806-809
50. Siervo-Sassi RR. Marrangoni AM. Feng X. Naoumova N. Winans M. Edwards RP. Lokshin A. Physiological and molecular effects of Apo2L/TRAIL and cisplatin in ovarian carcinoma cell lines. [Journal Article] Cancer Letters. 2003; 190(l):61-72.
51. Wu XX ,Ogawa O, Kakehi Y ,et al. TRAIL and chemotherapeutic drugs in cancer therapy. Vitam Horm, 2004; 67 (4) :365.
52. Chuntharapai A, Dodge K, Grimmer K, et al. Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J Immunol 2001; 166: 4891-4898.
53. Human Genome Sciences Reports on Progress of Clinical Trials and Announces Goals for 2005 at JP Morgan Healthcare Conference. Accessed January 24, 2005.
54. De Bono J, Attard G, Plummer R, et al. A phase I and pharmacokinetic (PK) study of an agonistic, fully human monoclonal antibody, HGSETR2, to the TNFalpha related apoptosis inducing ligand receptor 2 (TRAIL R2) in patients with advanced cancer. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 61.
55. Hotte SJ, Oza AM, Le LH, et al. HGS-ETR1, a fully human monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand death receptor 1 (TRAILR1) in patients with advanced solid cancer: results of a phase I trial. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 64.
56. Cohen RB, Meropol NJ, Padavic KM, et al. A phase I clinical trial of HGS-ETR1, an agonist monoclonal antibody to TRAILR1, in patients with advanced solid tumors. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 13.
57. Tolcher A. Translation targeting TRAIL receptors to the clinic. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 139-141.
58. Altucci L, Rossin A, Raffelsberger W, et al. Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat Med 2001; 7: 680-686.
59. Pierre Fenaux , Cbristine Cbomienne , and laurent Degos. All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. Seminars in Hematology, 2001 , 38 (1): 13-25.
60. Chen Z, Wang ZY, Chen SJ. Acute promyelocytic leukemia: cellular and molecular basis of differentiation and apoptosis. Pharmacol Ther 1997; 76: 141-149.
61. Chou WC, Dang CV. Acute promyelocytic leukemia: recent advances in therapy and molecular basis of response to arsenic therapies. Curr Opin Hematol 2005; 12: 1-6.
62. Zhu J, Chen Z, Lallemand-Breitenbach V, de The H. How acute promyelocytic leukaemia revived arsenic. Nat Rev Cancer 2002; 2: 705-713.
63. Hussein MA, Saleh M, Ravandi F, et al. Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma. Br J Haematol 2004;125:470-476.
64. Hermine O, Dombret H, Poupon J, et al. Phase II trial of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell leukemia/lymphoma. Hematol J 2004; 5: 130-134.
65. Vuky J, Yu R, Schwartz L, Motzer RJ. Phase II trial of arsenic trioxide in patients with metastatic renal cell carcinoma. Invest New Drugs 2002; 20: 327-330, 2002.
66. Ravagnan L, Marzo I, Costantini P, et al. Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore. Oncogene 1999; 18: 2537-2546.
67. Gebbia V, Borsellino N, Testa A, et al. Cisplatin and epirubicin plus oral lonidamine as first-line treatment for metastatic breast cancer: a phase II study of the Southern Italy Oncology Group (GOIM). Anticancer Drugs 1997; 8: 943-948.
68. Papaldo P, Lopez M, Cortesi E, et al. Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide. J Clin Oncol 2003; 21: 3462-3468.
69. De Lena M, Lorusso V, Latorre A, et al. Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase II study. Eur J Cancer 2001; 37: 364-368.
70. Portalone L, Lombardi A, Antilli A, et al. Treatment of inoperable non-small cell lung carcinoma stage IIIb and IV with cisplatin, epidoxorubicin, vindesine and lonidamine: a phase II study. Tumori 1999; 85:239-242.
71. De Marinis F, Rinaldi M, Ardizzoni A, et al. The role of vindesine and lonidamine in the treatment of elderly patients with advanced non-small cell lung cancer: a phase III randomized FONICAP trial. Italian Lung Cancer Task Force. Tumori 1999; 85: 177-182.
72. Oudard S, Carpentier A, Banu E, et al. Phase II study of lonidamine and diazepam in the treatment of recurrent glioblastoma multiforme. J Neurooncol 2003; 63: 81-86
73. Ackermann EJ, Taylor JK, Bennett CF. The role of antiapoptotic Bcl-2 family members in endothelial apoptosis elucidated with antisense oligonucleotides. J Biol Chem 1999; 274: 11245-11252.
74. Miayake H, Tolcher A, Gleave ME. Chemosensitization and delayed androgen-independent recurrence of prostate cancer with the use of antisense Bcl-2 oligodeoxynucleotides. J Natl Cancer Inst 2000; 92: 34-41.
75. Zangemeister-Wittke U, Leech SH, Olie RA, et al. A novel bispecific antisense oligonucleotide inhibiting both bcl-2 and bcl-xL expression efficiently induces apoptosis in tumor cells. Clin Cancer Res 2000; 6: 2547-2555.
76. Ferreira CG, Epping M, Kruyt FA, et al. Apoptosis: target of cancer therapy. Clin Cancer Res 2002; 8: 2024-2034.
77. Zaffaroni N, Daidone MG Survivin expression and resistance to anticancer treatments: perspectives for new therapeutic interventions. Drug Resist Updat 2002; 5: 65-72.
78. Reed JC. Apoptosis-regulating proteins as targets for drug discovery. Trends Mol Med 2001; 7: 314-319.
79. Li F. Role of survivin and its splice variants in tumorigenesis. Br J Cancer 2005; 92: 212-216.
80. Wu J, Ling X, Pan D, et al. Molecular mechanism of inhibition of survivin transcription by the GC-rich sequence selective DNA-binding antitumor agent, hedamycin: evidence of survivin downregulation associated with drug sensitivity. J Biol Chem 2005Jan 5
81. Wang L, Zhang GM, Feng ZH. Down regulation of survivin expression reversed multidrug resistance in adiamycin-resistant HL-60/ADR cell line. Acta Pharmacol Sin 2003; 24: 1235-1240.
82. Shen C,Buck A,Polat B, et al. Downregulation of survivin expression by induction of the effector cell protease receptor-1 reduces tumor growth potential and results in an increased sensitivity to anticancer agents in human colon cancer[J].Cancer Gene Ther. 2003; 10(5): 403-410;
83. Zhu HX, Zhou CQ, Zhang G, et al. Survivin mutants reverse the malignancy of Hela cells.Ai Zheng,2003,22(5):467-470.
84. Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans [J]. Nature, 1998; 391(6669): 806-811.
85. Wen, S. F., Mahavni, V., Quijano, E., et al. Assessment of p53 gene transfer and biological activities in a clinical study of adenovirus-p53 gene therapy for recurrent ovarian cancer. Cancer Gene Ther. 2003; 10: 224-238.
86. Post, L. E.. Selectively replicating adenoviruses for cancer therapy: an update on clinical development. Curr. Opin. Invest. Drugs 2002; 3: 1768-1772.
87. Bullock, A. N. and Fersht, A. R. Rescuing the function of mutant p53. Nat. Rev. Cancer 2001; 1, 68-76.
88. Abarzua, P., LoSardo, J. E., Gubler, M. L., et al. Restoration of the transcription activation function to mutant p53 in human cancer cells. Oncogene 1996; 13, 2477-2482.
89. Selivanova, G., Iotsova, V., Okan, I., et al. Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat. Med. 1997; 3, 632-638.
90. Selivanova, G., Ryabchenko, L., Jansson, E., et al. Reactivation of mutant p53 through interaction of a C-terminal peptide with the core domain. Mol. Cell Biol. 1999; 19, 3395-3402.
91. Kim, A. L., Raffo, A. J., Brandt-Rauf, P. W.,et al. Conformational and molecular basis for induction of apoptosis by a p53 C-terminal peptide in human cancer cells. J. Biol. Chem. 1999; 274, 34924-34931.
92. Friedler, A., Hansson, L. O., Veprintsev, D. B.,et al. A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. Proc. Natl. Acad. Sci. USA 2002; 99, 937-942.
93. Bykov, V. J., Issaeva, N., Shilov, A., et al. Restoration of the tumor suppressor function to mutant p53 by a lowmolecular- weight compound. Nat. Med. 2002; 8, 282-288.
94. Foster, B. A., Coffey, H. A., Morin, M. J., et al. Pharmacological rescue of mutant p53 conformation and function. Science 1999; 286, 2507-2510.
95. Wang, W., Takimoto, R., Rastinejad, F.,et al. Stabilization of p53 by CP-31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 20 or MDM2 binding. Mol. Cell. Biol. 2003; 23, 2171-2181.
96. Luu, Y., Bush, J., Cheung, K. J.,et al. The p53 stabilizing compound CP-31398 induces apoptosis by activating the intrinsic Bax/mitochondrial/caspase-9 pathway. Exp. Cell Res. 2002; 276, 214-222.
97. Rajkumar SV, Richardson PG, Hideshima T, Anderson RC. Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 2005; 23: 630-639.
98. Almond JB, Cohen GM. The proteasome: a novel target for cancer chemotherapy. Leukemia 2002; 16: 433-443.
99. Hideshima T, Chauhan D, Richardson P, et al. NF-kB as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277: 16639-16647.
2. Ambrosini G ,Adida C ,Altieri DC. A novel antiapoptsis gene ,survivin ,expressed in cancer and lmyphoma[J]. Nat Med,1997,3 (8) :917
3. Daniel SO ,J eft rey SS ,Colet te A ,et al. Control of apoptosis during angiogenesis by survivin expression in endothelial cells [J] . Am J Pat hol ,2000,156(2) :393.
4. Yaginuma, Y, Westphal, H. Abnormal structure and expression of p53 gene in human ovarian carcinoma cell lines. Cancer Res., 52:4196-4199, 1992
5. Safrit JT,Breech JS,Bonavida B.Sensitivity of drug-resistant human ovarian tumor cell lines to combined effects of tumor necrosis factors(TNF-α)and doxorubicin:failure of the combination to modulate the MDR phenotype.Gynecol Oncol, 1993 ;48(2):214
6. Pestell K. E., Medlow C. J., Titley J. C., Kelland L. R., Walton Mo I. Characterisation of the p53 status, BCL-2 expression and radiation and platinum drug sensitivity of a panel of human ovarian cancer cell lines. Int. J. Cancer, 77: 913-918, 1998.;
7. KM Henkels, JJ Turchi .Induction of apoptosis in cisplatin-sensitive and -resistant human ovarian cancer cell lines. Cancer Research, 1997: 57 (20) 4488-4492
8. Pestell K. E., Medlow C. J., Titley J. C., Kelland L. R., Walton M. I. Characterisation of the p53 status, BCL-2 expression and radiation and platinum drug sensitivity of a panel of human ovarian cancer cell lines. Int. J. Cancer, 77: 913-918, 1998.;
9. Wu G. S., El-Deity W. S. p53 and chemosensitivity. Nat. Med., 2: 255-256, 1996
10. Evan GL. A matter of life and cell death [J]. Science, 1998,281 (5381) : 131721312.
11．梁志清，卵巢癌化疗耐药机制研究进展中国实用妇科与产科杂志 2005年7月第21卷第7期，446-448
12. Lowe SW Cancer therapy and p53 [J].Curr Opin Oncol 1995. 7(6): 547 —553
13. Vogelstein, B., Lane, D. and Levine, A. J. (2000). Surfing the p53 network. Nature 408, 307-310.
14. OConnor PM,Jackman J ,Bae I ,et al. Characterization of the p53 tumor suppressor pathway in cell lines of the national cancer institute anticancer drug screen and correlations with the growth2inhibitory potency of 123 anticancer agents[J]. Cancer Res ,1997,57:4285-4300
15. Siddik ZH, Mims B, Lozano G, etal. Independent pathways of p53 induction by cisplatin and X-rays in a cisplatin-resistant ovarian tumor cell line. Cancer Res, 1998, 58 (4) : 698-703
16. Reles A, Wen WH, Schmider A. Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer. Clin Cancer Res, 2001, 7(10):2984-2997.
17. Sato S ,Kigawa J ,Minagawa Y,et al . Chemosensitivity and p532dependent apoptosis in epithelial ovarian carcinoma [J] . Cancer , 1999 , 86(7) :1307-1313.
18. Irie T ,Kigawa J ,Minagawa Y,et al . Alteration of a p53 gene status affects outcome of patients with recurrent ovarian cancer [J]. Oncology, 2000,58(3):237-241.
19. Ashkenazi, A. and Dixit, V. M. (1998). Death receptors: signaling and modulation. Science 281,1305-1308.
20. Newton, K. and Strasser, A. (2000) J. Exp. Med. 191,195- 200
21. Schuler, M., Bossy-Wetzel, E., Goldstein, J. C, Fitzgerald, P.and Green, D. R. (2000) J. Biol. Chem. 275, 7337-7342
22. Kuida, K., Haydar, T. F., Kuan, C.-Y., Gu, Y., Taya, C.,Karasuyama, H., Su, M. S. S., Rakic, P. and Flavell, R. A. (1998) Cell 94, 325-337
23. Hakem, R., Hakem, A., Duncan, G. S., Henderson, J. T.,Woo, M., Soengas, M. S., Elia, A., de al Pompa, J. L., Kagi, D., Khoo, W., et al. (1998) Cell 94, 339±352
24. Cecconi, F., Alvarez-Bolado, G., Meyer, B. I., Roth, K. A. and Gruss, P. (1998) Cell 94, 727-737.
25. Yoshida, H., Kong, Y.-Y., Yoshida, R., Elia, A. J., Hakem, A., Hakem, R., Penninger, J. M. and Mak, T. W. (1998) Cell 94, 739-750.
26. Soengas, M. S., Alarco! n, R. M., Yoshida, H., Giaccia, A. J., Hakem, R., Mak, T. W. and Lowe, S. W. (1999) Science 284, 156-159
27. Havell EA, Fiers W, North RJ. The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity. J Exp Med 1988; 167: 1067-1085.
28. Ogasawara J, Watanabe-Fukunaga R, Adachi M, et al. Lethal effect of the anti-Fas antibody in mice [erratum appears in Nature 1993;365:568]. Nature 1993; 364: 806-809
29. Kischkel FC, Lawwrence DA, Chuntharapai A, et al.Apo2L/TRAIL-dependent recruitment of endogenous FADD and Caspase-8 to death receptors 4 and 5.Immunity,2000,12(6):611-620
30. Shivapurkar N,Toyooka S, Toyooka KO, et al. Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types. Int J Cancer. 2004,109(5): 786 - 792
31.Miyashita T,Kawakami A, Nakashima T, et al. Osteoprotegerin(OPG) acts as an endogenous decoy receptor in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of fibroblastlike synovial cells. Clin Exp Immunol,2004,137(2):430-436
32. Gasparri, A. et al. Tumor pretargeting with avidin improves the therapeutic index of biotinylated tumor necrosis factor alpha in mouse models. Cancer Res. 59, 2917-2923 (1999).
33. Arap, W., Pasqualini, R. & Ruoslahti, E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279, 377-380 (1998).
34. Pasqualini, R., Koivunen, E. & Ruoslahti, E. Alpha v integrins as receptors for tumor targeting by circulating ligands. Nat. Biotechnol. 15, 542-546 (1997).
35. Siervo-Sassi RR. Marrangoni AM. Feng X. Naoumova N. Winans M. Edwards RP. Lokshin A. Physiological and molecular effects of Apo2L/TRAIL and cisplatin in ovarian carcinoma cell lines. [Journal Article] Cancer Letters. 190(1):61-72, 2003 Feb 10.
36. Wu XX ,Ogawa O ,Kakehi Y ,et al. TRAIL and chemotherapeutic drugs in cancer therapy [J] . Vitam Horm ,2004 ,67 (4) :365.
37. Sean K. Kelley, Louise A. Harris, David Xie, Laura DeForge, Klara Totpal, Jeanine Bussiere and Judith A. Fox, Preclinical Studies to Predict the Disposition of Apo2L/Tumor Necrosis Factor-Related Apoptosis-inducing Ligand in Humans: Characterization of in Vivo Efficacy, Pharmacokinetics, and Safety, 2001. 299(1), 31-38)
38. Andreas Evdokiou Stelios Bouralexis , Gerald J. Atkins , Chemotherapeutic agents sensitize osteogenic sarcoma cells, but not normal human bone cells, to apo21/trail-induced apoptosis .Cancer Cell Biology .2002 99(4) , 491 - 504.
39. (Eui-Cheol Shin1, Young Rim Seong2,Chul Hoon Kim3,et al Human hepatocellular carcinoma cells resist to TRAIL-induced apoptosis, and the resistance is abolished by cisplatin. EXPERIMENTAL and MOLECULAR MEDICINE, 2002. 34( 2), 114-122, )
40. Jo M, Kim TH, Seol DW, et al. Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med 2000;6:564-7
41. Walczak H, Miller RE, Ariail K, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo . Nat Med 1999;5: 157-63.
42. Denis Lane, Andre'anne Cartier, Sylvain L'Espe'rance, Marceline Co^te',Claudine Rancourt, and Alain Piche. Differential induction of apoptosis by tumor necrosis factor-relatedapoptosis-inducing ligand in human ovarian carcinoma cells, Gynecologic Oncology 93 (2004) 594-604, 594-604
43. Chuntharapai A, Dodge K, Grimmer K, et al. Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J Immunol 2001; 166: 4891-4898.
44. Human Genome Sciences Reports on Progress of Clinical Trials and Announces Goals for 2005 at JP Morgan Healthcare Conference. Accessed January 24,2005.
45. De Bono J, Attard G, Plummer R, et al. A phase I and pharmacokinetic (PK) study of an agonistic, fully human monoclonal antibody, HGSETR2, to the TNFalpha related apoptosis inducing ligand receptor 2 (TRAIL R2) in patients with advanced cancer [abstract]. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 61.
46. Hotte SJ, Oza AM, Le LH, et al. HGS-ETR1, a fully human monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand death receptor 1 (TRAILR1) in patients with advanced solid cancer: results of a phase I trial [abstract]. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 64.
47. Cohen RB, Meropol NJ, Padavic KM, et al. A phase I clinical trial of HGS-ETR1, an agonist monoclonal antibody to TRAILR1, in patients with advanced solid tumors. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 13.
48. Tolcher A. Translation targeting TRAIL receptors to the clinic. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 139-141.
1. Green DR. Apoptotie pathways: the roads to ruin [J] Cell.1 998; 94(6): 695—698
2. Soo-Jung P, Ching-Haung W, John DG, et al. Taxol Induces Caspase- 10-dependent Apoptosis. [J] Biol Chem, 2004; 279( 49): 51057- 51067
3. Merei H, Ine B, Tijdens, Gerard J. et al. Differential Regulation of Doxorubicin-induced Mitochondrial Dysfunction and Apoptosis by Bcl-2 in Mammary Adenocarcinoma. Cells, 2002; 277(27): 35869-35879
4. Kischkel FC, Lawwrence DA, Chuntharapai A, et al. Apo2L/RAIL- dependent recruitment of endogenous FADD and Caspase-8 to death receptors 4 and 5. Immunity, 2000; 12(6): 611-620
5. Shivapurkar N, Toyooka S, Toyooka KO, et al. Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types. Int J Cancer, 2004; 109(5): 786 - 792
6. Miyashita T, Kawakami A, Nakashima T, et al. Osteoprotegerin (OPG) acts as an endogenous decoy receptor in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis of fibroblastlike synovial cells. Clin Exp Immunol, 2004; 137(2): 430-436
7. Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat. Rev. Cancer, 2002; 2: 647-656.
8. Kuwana T., Mackey MR., Perkins G., et al. Bid, Bax and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell ,2002; 111:331-342.
9. Kelekar A, Thompson CB. Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol, 1998; 8: 324-330.
10. Yu J., Zhang L., Hwang P., et al. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol. Cell, 2001; 7: 673-682.
11. Bouillet P, Straser A. BH3-only proteins - evolutionarily conserved pro-apoptotic Bcl-2 family members essential for initiating programmed cell death. J. Cell Sci., 2002 ;115: 1567-1574.
12. Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell, 2001; 7: 683-694
13. Yu J, Wang Z., Kinzler K, et al. PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc. Natl. Acad. Sci. USA, 2003; 100: 1931-1936.
14. Kim TH, Zhao Y, Barber MJ, et al. Bid-induced cytochrome release is mediated by a pathway independent of mitochondrial permeability transition pore and Bax. J Biol Chem, 2000; 275: 39474
15. Oda E, Ohki R., Murasawa H., et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science, 2000; 288: 1053-1058.
16. Yoshide B, Kang YY, Yoshide R, et al. Apaf-1 is required for mitochondrial pathways of apoptosis and brain development [J].Cell, 1998; 94:739-750.
17. Adams JM, Cory S. Apoptosomes: engines for caspase activation. Curr. Opin. Cell Biol, 2002; 14: 715-720.
18. Daugas E, Susin SA, Zamzami N, et al. Mitochondria-nuclear translocation of AIF in apoptosis and necrosis[J]. FASEB, 2000, 14(5): 729-739.
19. Patterson S D, Spahr C S, Daudas E, et al. Mass spectrometric identification of proteins released from mitochondria undergoing permeability transition[J].Cell Death Differ, 2000, 7(2): 137-144.
20. Du C, Fang M, Li Y, et al. Smac a mitochondrial protein that promotes cytochrome C-dependent caspase activation by eliminating LAP inhibition[J].Cell,2000,102:33-42.
21. Verhagen A M, Ekert P. G.Identification of DLABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing LAP proteins[J]. Cell,2000,102(1):43-53.
22. Giaccia AJ, Kastan MB. The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev, 1998; 12: 2973-2983.
23. Vogt SR, Haupt Y. The cellular response to p53: the decision between life and death. Oncogene, 1999;18: 6145-6157.
24. Thornborrow E C, Patel S, Mastropietro AE, et al A conserved intronic response element mediates direct p53-dependent transcnptional activation of both the human and murine bax genes. Oncogene, 2002; 21: 990-999.
25. Marchenko ND, Zaika A, Moll UM. Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J. Biol. Chem, 2000; 275: 16202-16212
26. Mihara M, Erster S, Zaika A, et al. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell, 2003 ;11: 577-590.
27. Kannan, K., Kaminski, N., Rechavi, G., et al. DNA microarray analysis of genes involved mediated apoptosis: activation of Apaf-1. Oncogene 2001; 20, 3449-3455.
28. Moroni, M. C, Hickman, E. S., Denchi, E. L., et al. Apaf-1 is a transcnptional target for E2F and p53. Nat. Cell Biol. 2001; 3, 552-558
29. Robles, A. I, Bemmels, N. A., Foraker, A. B. et al. APAF-1 is a transcnptional target of p53 in DNA damage-induced apoptosis. Cancer Res. 2001; 61, 6660-6664.
30. Rozenfeld-Granot, G., Krishnamurthy, J., Kannan, K., et al. A positive feedback mechanism in the transcnptional activation of Apaf-1 by p53 and the coactivator Zac-1. Oncogene 2002; 21, 1469-1476.
31. Ding, H. F., McGill, G., Rowan, S., et al. Oncogene-dependent regulation of caspase activation by p53 protein in a cell-free system. J. Biol. Chem. 1998; 273, 28378-28383.
32. Varfolomeev, E. E., Schuchmann, M., Luria, V., Chiannilkulchai, N., Beckmann, J. S., Mett, I. L., Rebrikov, D., Brodianski, V. M., Kemper, O. C, Kollet, O. et al. (1998). Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo 1, and DR3 and is lethal prenatally. Immunity 9, 267-276.
33. MacLachlan, T. K. and El-Deiry, W. S. Apoptotic threshold is lowered by p53 transactivation of caspase-6. Proc. Natl. Acad. Sci. USA 2002; 99, 9492-9497.
34. Galande, S., Dickinson, L. A., Mian, I. S., et al. SATB1 cleavage by caspase 6 disrupts PDZ domainmediated dimerization, causing detachment from chromatin early in T-cell apoptosis. Mol. Cell. Biol. 2001; 21, 5591-5604.
35. Fuchs, E. J., McKenna, K. A. and Bedi, A. p53-dependent DNA damage-induced apoptosis requires Fas/APO-1-independent activation of CPP32beta. Cancer Res. 1997; 57, 2550-2554
36. O'Connor, L., Harris, A. W. and Strasser, A. CD95 (Fas/APO-1) and p53 signal apoptosis independently in diverse cell types. Cancer Res. 2000; 60,1217-1220.
37. Ghosh S, Karin M. Missing pieces in the NF-κB puzzle. Cell, 2002; 109(suppl): S81-S96
38. Chen C, Edelstein LC, Gelinas C. The Rel/ NF-κB family directly activates expression of the apotosis inhibitor Bcl-x. Mol Cell Biol, 2000; 20(8):2687-2695
39. Greten FR, Echmann L, Greten TF, et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell, 2004; 118(3):285-296
40. De Moissac D, Mustapha S, Greenberg AH, et al. Bcl-2 activates the transcription factor NFkappaB through the degradation of the cytoplasmic inhibitor IkappaBalpha.J Biol Chem. 1998 Sep 11; 273(37): 23946-51.
41. Li L, Liao J, Ruland J, et al. A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control.Proc Natl Acad Sci U S A. 2001 Feb 13;98(4): 1619-24
42. Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 2000; 19: 6680-6686.
43. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296: 1655-1657
44. Mayo, L. D. and Dormer, D. B. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem. Sci. 2002; 27, 462-467.
45. Testa, J. R. and Bellacosa, A. AKT plays a central role in tumorigenesis. Proc. Natl. Acad. Sci. USA 2001; 98,10983-10985.
46. Tolcher AW. Regulators of apoptosis as anticancer targets. Hematol Oncol Clin North Am 2002; 16: 1255-1267.
47. Ferreira CG, Epping M, Kruyt FA, et al. Apoptosis: target of cancer therapy. Clin Cancer Res 2002; 8: 2024-2034.
48. Havell EA, Fiers W, North RJ. The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity. J Exp Med 1988; 167: 1067-1085.
49. Ogasawara J, Watanabe-Fukunaga R, Adachi M, et al. Lethal effect of the anti-Fas antibody in mice. Nature 1993; 364: 806-809
50. Siervo-Sassi RR. Marrangoni AM. Feng X. Naoumova N. Winans M. Edwards RP. Lokshin A. Physiological and molecular effects of Apo2L/TRAIL and cisplatin in ovarian carcinoma cell lines. [Journal Article] Cancer Letters. 2003; 190(l):61-72.
51. Wu XX ,Ogawa O, Kakehi Y ,et al. TRAIL and chemotherapeutic drugs in cancer therapy. Vitam Horm, 2004; 67 (4) :365.
52. Chuntharapai A, Dodge K, Grimmer K, et al. Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J Immunol 2001; 166: 4891-4898.
53. Human Genome Sciences Reports on Progress of Clinical Trials and Announces Goals for 2005 at JP Morgan Healthcare Conference. Accessed January 24, 2005.
54. De Bono J, Attard G, Plummer R, et al. A phase I and pharmacokinetic (PK) study of an agonistic, fully human monoclonal antibody, HGSETR2, to the TNFalpha related apoptosis inducing ligand receptor 2 (TRAIL R2) in patients with advanced cancer. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 61.
55. Hotte SJ, Oza AM, Le LH, et al. HGS-ETR1, a fully human monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand death receptor 1 (TRAILR1) in patients with advanced solid cancer: results of a phase I trial. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 64.
56. Cohen RB, Meropol NJ, Padavic KM, et al. A phase I clinical trial of HGS-ETR1, an agonist monoclonal antibody to TRAILR1, in patients with advanced solid tumors. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 13.
57. Tolcher A. Translation targeting TRAIL receptors to the clinic. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004. Eur J Cancer Suppl 2004; 2: 139-141.
58. Altucci L, Rossin A, Raffelsberger W, et al. Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat Med 2001; 7: 680-686.
59. Pierre Fenaux , Cbristine Cbomienne , and laurent Degos. All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. Seminars in Hematology, 2001 , 38 (1): 13-25.
60. Chen Z, Wang ZY, Chen SJ. Acute promyelocytic leukemia: cellular and molecular basis of differentiation and apoptosis. Pharmacol Ther 1997; 76: 141-149.
61. Chou WC, Dang CV. Acute promyelocytic leukemia: recent advances in therapy and molecular basis of response to arsenic therapies. Curr Opin Hematol 2005; 12: 1-6.
62. Zhu J, Chen Z, Lallemand-Breitenbach V, de The H. How acute promyelocytic leukaemia revived arsenic. Nat Rev Cancer 2002; 2: 705-713.
63. Hussein MA, Saleh M, Ravandi F, et al. Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma. Br J Haematol 2004;125:470-476.
64. Hermine O, Dombret H, Poupon J, et al. Phase II trial of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell leukemia/lymphoma. Hematol J 2004; 5: 130-134.
65. Vuky J, Yu R, Schwartz L, Motzer RJ. Phase II trial of arsenic trioxide in patients with metastatic renal cell carcinoma. Invest New Drugs 2002; 20: 327-330, 2002.
66. Ravagnan L, Marzo I, Costantini P, et al. Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore. Oncogene 1999; 18: 2537-2546.
67. Gebbia V, Borsellino N, Testa A, et al. Cisplatin and epirubicin plus oral lonidamine as first-line treatment for metastatic breast cancer: a phase II study of the Southern Italy Oncology Group (GOIM). Anticancer Drugs 1997; 8: 943-948.
68. Papaldo P, Lopez M, Cortesi E, et al. Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide. J Clin Oncol 2003; 21: 3462-3468.
69. De Lena M, Lorusso V, Latorre A, et al. Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase II study. Eur J Cancer 2001; 37: 364-368.
70. Portalone L, Lombardi A, Antilli A, et al. Treatment of inoperable non-small cell lung carcinoma stage IIIb and IV with cisplatin, epidoxorubicin, vindesine and lonidamine: a phase II study. Tumori 1999; 85:239-242.
71. De Marinis F, Rinaldi M, Ardizzoni A, et al. The role of vindesine and lonidamine in the treatment of elderly patients with advanced non-small cell lung cancer: a phase III randomized FONICAP trial. Italian Lung Cancer Task Force. Tumori 1999; 85: 177-182.
72. Oudard S, Carpentier A, Banu E, et al. Phase II study of lonidamine and diazepam in the treatment of recurrent glioblastoma multiforme. J Neurooncol 2003; 63: 81-86
73. Ackermann EJ, Taylor JK, Bennett CF. The role of antiapoptotic Bcl-2 family members in endothelial apoptosis elucidated with antisense oligonucleotides. J Biol Chem 1999; 274: 11245-11252.
74. Miayake H, Tolcher A, Gleave ME. Chemosensitization and delayed androgen-independent recurrence of prostate cancer with the use of antisense Bcl-2 oligodeoxynucleotides. J Natl Cancer Inst 2000; 92: 34-41.
75. Zangemeister-Wittke U, Leech SH, Olie RA, et al. A novel bispecific antisense oligonucleotide inhibiting both bcl-2 and bcl-xL expression efficiently induces apoptosis in tumor cells. Clin Cancer Res 2000; 6: 2547-2555.
76. Ferreira CG, Epping M, Kruyt FA, et al. Apoptosis: target of cancer therapy. Clin Cancer Res 2002; 8: 2024-2034.
77. Zaffaroni N, Daidone MG Survivin expression and resistance to anticancer treatments: perspectives for new therapeutic interventions. Drug Resist Updat 2002; 5: 65-72.
78. Reed JC. Apoptosis-regulating proteins as targets for drug discovery. Trends Mol Med 2001; 7: 314-319.
79. Li F. Role of survivin and its splice variants in tumorigenesis. Br J Cancer 2005; 92: 212-216.
80. Wu J, Ling X, Pan D, et al. Molecular mechanism of inhibition of survivin transcription by the GC-rich sequence selective DNA-binding antitumor agent, hedamycin: evidence of survivin downregulation associated with drug sensitivity. J Biol Chem 2005Jan 5
81. Wang L, Zhang GM, Feng ZH. Down regulation of survivin expression reversed multidrug resistance in adiamycin-resistant HL-60/ADR cell line. Acta Pharmacol Sin 2003; 24: 1235-1240.
82. Shen C,Buck A,Polat B, et al. Downregulation of survivin expression by induction of the effector cell protease receptor-1 reduces tumor growth potential and results in an increased sensitivity to anticancer agents in human colon cancer[J].Cancer Gene Ther. 2003; 10(5): 403-410;
83. Zhu HX, Zhou CQ, Zhang G, et al. Survivin mutants reverse the malignancy of Hela cells.Ai Zheng,2003,22(5):467-470.
84. Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans [J]. Nature, 1998; 391(6669): 806-811.
85. Wen, S. F., Mahavni, V., Quijano, E., et al. Assessment of p53 gene transfer and biological activities in a clinical study of adenovirus-p53 gene therapy for recurrent ovarian cancer. Cancer Gene Ther. 2003; 10: 224-238.
86. Post, L. E.. Selectively replicating adenoviruses for cancer therapy: an update on clinical development. Curr. Opin. Invest. Drugs 2002; 3: 1768-1772.
87. Bullock, A. N. and Fersht, A. R. Rescuing the function of mutant p53. Nat. Rev. Cancer 2001; 1, 68-76.
88. Abarzua, P., LoSardo, J. E., Gubler, M. L., et al. Restoration of the transcription activation function to mutant p53 in human cancer cells. Oncogene 1996; 13, 2477-2482.
89. Selivanova, G., Iotsova, V., Okan, I., et al. Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat. Med. 1997; 3, 632-638.
90. Selivanova, G., Ryabchenko, L., Jansson, E., et al. Reactivation of mutant p53 through interaction of a C-terminal peptide with the core domain. Mol. Cell Biol. 1999; 19, 3395-3402.
91. Kim, A. L., Raffo, A. J., Brandt-Rauf, P. W.,et al. Conformational and molecular basis for induction of apoptosis by a p53 C-terminal peptide in human cancer cells. J. Biol. Chem. 1999; 274, 34924-34931.
92. Friedler, A., Hansson, L. O., Veprintsev, D. B.,et al. A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. Proc. Natl. Acad. Sci. USA 2002; 99, 937-942.
93. Bykov, V. J., Issaeva, N., Shilov, A., et al. Restoration of the tumor suppressor function to mutant p53 by a lowmolecular- weight compound. Nat. Med. 2002; 8, 282-288.
94. Foster, B. A., Coffey, H. A., Morin, M. J., et al. Pharmacological rescue of mutant p53 conformation and function. Science 1999; 286, 2507-2510.
95. Wang, W., Takimoto, R., Rastinejad, F.,et al. Stabilization of p53 by CP-31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 20 or MDM2 binding. Mol. Cell. Biol. 2003; 23, 2171-2181.
96. Luu, Y., Bush, J., Cheung, K. J.,et al. The p53 stabilizing compound CP-31398 induces apoptosis by activating the intrinsic Bax/mitochondrial/caspase-9 pathway. Exp. Cell Res. 2002; 276, 214-222.
97. Rajkumar SV, Richardson PG, Hideshima T, Anderson RC. Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 2005; 23: 630-639.
98. Almond JB, Cohen GM. The proteasome: a novel target for cancer chemotherapy. Leukemia 2002; 16: 433-443.
99. Hideshima T, Chauhan D, Richardson P, et al. NF-kB as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277: 16639-16647.