Current status of the molecular mechanisms of anticancer drug-induced apoptosis: The contribution of molecular-level analysis to cancer chemotherapy

Cancer Chemotherapy and Pharmacology

Volumn 50, Issue 5, 2002, Pages 343-352

  Kim, Ryungsa ^a   Tanabe, Kazuaki ^a   Uchida, Yoko ^a   Emi, Manabu ^a   Inoue, Hideki ^a   Toge, Tetsuya ^a  

^a HIROSHIMA UNIVERSITY   (Japan)

Author keywords

Anticancer drugs; Apoptosis; Cancer chemotherapy; Drug sensitivity; Molecular mechanisms

Indexed keywords

ANION CHANNEL; ANTHRACYCLINE ANTIBIOTIC AGENT; APOPTOTIC PROTEASE ACTIVATING FACTOR 1; CASPASE 3; CASPASE 9; CYTOCHROME C; DEOXYADENOSINE TRIPHOSPHATE; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; FLUOROURACIL; HEAT SHOCK PROTEIN; PROTEIN; PROTEIN BAK; PROTEIN BAX; PROTEIN BID; PROTEIN KINASE B; SURVIVIN; TAXANE DERIVATIVE; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER CHEMOTHERAPY; CELL SURVIVAL; DRUG SENSITIVITY; HUMAN; MITOCHONDRIAL MEMBRANE; MOLECULAR DYNAMICS; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; PROTEIN SECRETION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION;

ANTINEOPLASTIC AGENTS; APOPTOSIS; BIOLOGICAL TRANSPORT; CYTOCHROME C GROUP; DRUG DESIGN; FORECASTING; GENE EXPRESSION REGULATION; HUMANS; INTRACELLULAR MEMBRANES; ION CHANNELS; MITOCHONDRIA; MODELS, BIOLOGICAL; NEOPLASM PROTEINS; NEOPLASMS; OLIGONUCLEOTIDES, ANTISENSE; RECEPTORS, TUMOR NECROSIS FACTOR; SIGNAL TRANSDUCTION;

EID: 0036449793     PISSN: 03445704     EISSN: None     Source Type: Journal    
DOI: 10.1007/s00280-002-0522-7     Document Type: Review

References (115)

1. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: A basic phenomenon with wide-raging implications in tissue kinetics. Br J Cancer 26:239
2. Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309
3. Gross A, McDonnell JM, Korsmeyer SJ (1999) BCL-2 family members and mitochondria in apoptosis. Genes Dev 13:1899
4. Evan G, Littlewood T (1998) A matter of life and cell death. Science 281:1317
5. Thornberry NA, Lazebnik Y (1998) Caspases: Enemies within. Science 281:1312
6. Olopade OI, Adeyanju MO, Safa AR, Hagos F, Mick R, Thompson CB, Recant WM (1997) Overexpression of BCL-x protein in primary breast cancer is associated with high tumor grade and nodal metastases. Cancer J Sci Am 3:230
7. Ferreira CG, Tolis C, Giaccone G (1999) p53 and chemosensitivity. Ann Oncol 10:1011
8. Reed JC (1998) Bcl-2 family proteins. Oncogene 17:3225
9. Cao DT, Korsmeyer SJ (1998) Bcl-2 family: Regulators of cell death. Annu Rev Immunol 16:395
10. Salomons GS, Smets LA, Verwijs-Janssen M, Hart AA, Haarman EG, Kaspers GJ, Wering EV, Der Does-Van Den Berg AV, Kamps WA (1999) Bcl-2 family members in childhood acute lymphoblastic leukemia: Relationships with features at presentation, in vitro and in vivo drug response and long-term clinical outcome. Leukemia 13:1574
11. Cassinelli G, Supino R, Perego P, Polizzi D, Lanzi C, Pratesi G (2001) A role for loss of p53 function in sensitivity of ovarian carcinoma cells to taxanes. Int J Cancer 92:738
12. Kim R, Nishimoto N, Inoue H, Toge T (2000) An analysis of the therapeutic efficacy of protracted infusion of low-dose 5-fluorouracil and cisplatin in advanced gastric cancer. J Infect Chemother 6:222
13. Riedl SJ, Fuentes-Prior P, Renatus M, Kairies N, Krapp S, Huber R, Salvesen GS, Bode W (2001) Structural basis for the activation of human procaspase-7. Proc Natl Acad Sci U S A 98:14790
14. Nagata S (2000) Apoptotic DNA fragmentation. Exp Cell Res 256:12
15. Lechardeur D, Drzymala L, Sharma M, Zylka D, Kinach R, Pacia J, Hicks C, Usmani N, Rommens JM, Lukacs GL (2000) Determinants of the nuclear localization of the heterodimeric DNA fragmentation factor (ICAD/CAD). J Cell Biol 150:321
16. Sahara S, Aoto M, Eguchi Y, Imamoto N, Yoneda Y, Tsujimoto Y (1999) Acinus is a caspase-3-activated protein required for apoptotic chromatin condensation. Nature 401:168
17. Adams JM, Cory S (1998) The Bcl-2 protein family: Arbiters of cell survival. Science 281:1322
18. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng T-I, Jones DP, Wang X (1997) Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science 275:1129
19. Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science 275:1132
20. Krajewski S, Blomqvist C, Franssila K, Krajewska M, Wasenius VM, Niskanen E, Nordling S, Reed JC (1995) Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in woman with metastatic breast adenocarcinoma. Cancer Res 55:4471
21. Ogura E, Senzaki H, Yamamoto D, Yoshida R, Takada H, Hioki K, Tsubura A (1999) Prognostic significance of Bcl-2, Bcl-XL/S, Bax and Bak expressions in colorectal carcinomas. Oncol Rep 6:365
22. Nomura M, Shimizu S, Ito T, Narita M, Matsuda H, Tsujimoto Y (1999) Apoptotic cytosol facilitates Bax translocation to mitochondria that involves cytosolic factor regulated by Bcl-2. Cancer Res 59:5542
23. Tsujimoto Y, Shimizu S (2000) VDAC regulation by the Bcl-2 family of proteins. Cell Death Differ 7:1174
24. Wang GQ, Gastman BR, Wieckowski E, Golstein LA, Gambotto A, Kim TH, Fang B, Rabinovitz A, Yin XM, Rabinowich H (2001) A role for mitochondrial Bak in apoptotic response to anticancer drugs: J Biol Chem 276:34307
25. Nechushtan A, Smith CL, Lamensdorf I, Yoon SH, Youle RJ (2001) Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. J Cell Biol 153:1265
26. Shimizu S, Narita M, Tsujimoto Y (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399:483
27. Saito M, Korsmeyer SJ, Schlesinger PH (2000) BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Nat Cell Biol 2:553
28. Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB (1997) Bcl-XL regulates the membrane potential and volume homeostasis of mitochondria. Cell 91:627
29. Shimizu S, Matsuoka Y, Shinohara Y, Yoneda Y, Tsujimoto Y (2001) Essential role of voltage-dependent anion channel in various forms of apoptosis in mammalian cells. J Cell Biol 152:237
30. Schendel SL, Xie Z, Montal MO, Matsuyama S, Montal M, Reed JC (1997) Channel formation by antiapoptotic protein Bcl-2. Proc Natl Acad Sci U S A 94:5113
31. Minn AJ, Velez P, Schendel SL, Liang H, Muchmore SW, Fesik SW, Fill M, Thompson CB (1997) Bcl-XL forms an ion channel in synthetic lipid membranes. Nature 385:353
32. Narita M, Shimizu S, Ito T, Chittenden T, Lutz RJ, Matsuda H, Tsujimoto Y (1998) Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc Natl Acad Sci U S A 95:14681
33. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemeri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates apoptotic protease cascade. Cell 91:479
34. Hu Y, Benedict MA, Wu D, Inohara N, Nunez G (1998) Caspase 9, Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase 9 activation. Proc Natl Acad Sci U S A 95:4386
35. Green DR (1998) Apoptotic pathways: The roads to ruin. Cell 94:695
36. Boldin MP, Goncharow TM, Goltsev YV, Wallach D (1996) Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1 and TNF receptor-induced cell death. Cell 85:803
37. Mizuo M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM (1996) FLICE, a noel FADD-homologous ICE/CED-3 like protease, is required to CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85:817
38. Suliman A, Lam A, Datta R, Srivastava RK (2001) Intracellular mechanisms of TRAIL: Apoptosis through mitochondrial-dependent and -independent pathways. Oncogene 20:2122
39. Scaffidi C, Schmitz I, Zha J, Korsmeyer SJ, Krammer PH, Peter ME (1999) Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. J Biol Chem 274:22532
40. Fulda S, Meyer E, Friesen C, Susin SA, Kroemer G, Debatin KM (2001) Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis. Oncogene 20:1063
41. Page C, Lin HJ, Jin Y, Castle VP, Nunez G, Huang M, Lin J (2000) Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis. Anticancer Res 20:407
42. Nakashio A, Fujita N, Rokudai S, Sato S, Tsuruo T (2000) Prevention of phosphatidylinositol 3′-kinase-Akt survival signaling pathway during topotecan-induced apoptosis. Cancer Res 60:5303
43. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-XL. Cell 87:619
44. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231
45. Zhou H, Li XM, Meinkoth J, Pittman RN (2000) Akt regulates cell survival and apoptosis at a postmitochondrial level. J Cell Biol 151:483
46. Asselin E, Mills GB, Tsang BK (2001) XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells. Cancer Res 61:1862
47. Jaattela M, Wissing D, Kokholm K, Kallunki T, Egeblad M (1998) Hsp70 exerts its anti-apoptotic function down-stream of caspase-3-like proteases. EMBO J 17:6124
48. Mairesse N, Horman S, Mosselmans R, Galand P (1996) Antisense inhibition of the 27 kDa heat shock protein production affects growth rate and cytoskeletal organization in MCF-7 cells. Cell Biol Int 20:205
49. Garrido C, Bruey J-M, Fromentin A, Hammann A, Arrigo AP, Solary E (1999) HSP27 inhibits cytochrome c-dependent activation of procaspase-9. FASEB J 13:2061
50. Kaur J, Kaur J, Ralhan R (2000) Induction of apoptosis by abrogation of HSP70 expression in human oral cancer cells. Int J Cancer 85:1
51. Nylandsted J, Rohde M, Brand K, Bastholm L, Elling F, Jaattela M (2000) Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. Proc Natl Acad Sci U S A 87:7871
52. Ambrosini G, Adida C, Altieri DC (1997) A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3:917
53. Kawasaki H, Altieri DC, Lu CD, Toyoda M, Tenjo T, Tanigawa N (1998) Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. Cancer Res 58:5071
54. Lu CD, Altieri DC, Tanigawa N (1998) Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res 58:1808
55. Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, Reed JC (1998) IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res 58:5315
56. Tanaka K, Iwamoto S, Gon G, Nohara T, Iwamoto M, Tanigawa N (2000) Expression of survivin and its relationship to loss of apoptosis in breast carcinoma. Clin Cancer Res 6:127
57. Kappler M, Kohler T, Kampf C, Diestelkotter P, Wurl P, Schmitz M, Bartel F, Lautenschlager C, Rieber EP, Schmidt H, Bache M, Taubert H, Meye A (2001) Increased survivin transcript levels: An independent negative predictor of survival in soft tissue sarcoma patients. Int J Cancer 95:360
58. Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC (1998) Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396:580
59. Shin S, Sung BJ, Cho YS, Kim HJ, Ha NC, Hwang JI, Chung CW, Jung YK, Oh BH (2001) An antiapoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry 40:1117
60. O'Connor DS, Grossman D, Plescia J, Li F, Zhang H, Villa A, Tognin S, Marchisio PC, Altieri DC (2000) Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc Natl Acad Sci U S A 97:13103
61. Ikeguchi M, Liu J, Kaibara N (2002) Expression of survivin mRNA and protein in gastric cancer cell line (MKN-45) during cisplatin treatment. Apoptosis 7:23
62. Olie RA, Simoes-Wust AP, Baumann B, Leech SH, Fabbro D, Stahel RA, Zangemeister-Wittke U (2000) A novel antisense oligonucleotide targeting survivin expression induces apoptosis and sensitizes lung cancer cells to chemotherapy. Cancer Res 60:2805
63. Jiang X, Wilford C, Duensing S, Munger K, Jones G, Jones D (2001) Participation of survivin in mitotic and apoptotic activities of normal and tumor-derived cells. J Cell Biochem 83:342
64. Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M (2002) Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem 277:3247
65. LaCasse EC, Baird S, Korneluk RG, MacKenzie AE (1998) The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene 17:3247
66. Jaattela M, Mourizen H, Elling F, Bastholm L (1996) A20 zinc finger protein inhibitors TNF and IL-1 signaling. J Immunol 156:1166
67. Wong GHW, Goeddel DV (1998) Induction of manganous superoxide dismutase by tumor necrosis factor: Possible protective mechanism. Science 242:941
68. Weldon CB, Burow ME, Rolfe KW, Clayton JL, Jaffe BM, Beckman BS (2001) NF-kappa B-mediated chemoresistance in breast cancer cells. Surgery 130:143
69. Trauzold A, Wermann H, Arlt A, Schutze S, Schafer H, Oestern S, Roder C, Ungefroren H, Lampe E, Heinrich M, Walczak H, Kalthoff H (2001) CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-kappaB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells. Oncogene 20:4258
70. Catz SD, Johnson JL (2001) Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene 20:7342
71. Bentires-Alj M, Dejardin E, Viatour P, Van Lint C, Froesch B, Reed JC, Merville MP, Bours V (2001) Inhibition of the NF-kappa B transcription factor increases Bax expression in cancer cell lines. Oncogene 20:2805
72. Nakayama H, Ikebe T, Beppu M, Shirasuna K (2001) High expression levels of nuclear factor kappaB, IkappaB kinase alpha and Akt kinase in squamous cell carcinoma of the oral cavity. Cancer 92:3037
73. De Smaele E, Zazzeroni F, Papa S, Nguyen DU, Jin R, Jones J, Cong R, Franzoso G (2001) Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature 414:308
74. Javelaud D, Besancon F (2001) NF-kappa B activation results in rapid inactivation of JNK in TNF alpha-treated Ewing sarcoma cells: A mechanism for the anti-apoptotic effect of NF-kappa B. Oncogene 20:4365
75. Spalding AC, Jotte RM, Scheinman RI, Geraci MW, Clarke P, Tyler KL, Johnson GL (2002) TRAIL and inhibitors of apoptosis are opposing determinants for NF-kappaB-dependent, genotoxin-induced apoptosis of cancer cells. Oncogene 21:260
76. Huang Y, Fan W (2002) IkappaB kinase activation is involved in regulation of paclitaxel-induced apoptosis in human tumor cell lines. Mol Pharmacol 61:105
77. Habraken Y, Piret B, Piette J (2001) S phase dependence and involvement of NF-kappaB activating kinase to NF-kappaB activation by camptothecin. Biochem Pharmacol 62:603
78. Strobel T, Swanson L, Korsmeyer S, Cannistra SA (1996) BAX enhances paclitaxel-induced apoptosis through a p53-independent pathway. Proc Natl Acad Sci U S A 93:14094
79. Kim R, Ohi Y, Inoue H, Toge T (2000) Enhancement of chemotherapeutic agent induced-apoptosis associated with activation of c-Jun N-terminal kinase 1 and caspase 3 (CPP32) in bax-transfected gastric cancer cells. Anticancer Res 20:439
80. Kim R, Minami K, Nishimoto N, Toge T (2001) Enhancement of antitumor effect by intratumoral administration of bax gene in combination with anticancer drugs in gastric cancer. Int J Oncol 18:363
81. Sumantran VN, Ealovega MW, Nunez G, Clarke MF, Wicha MS (1995) Overexpression of bcl-Xs sensitizes MCF-7 cells to chemotherapy-induced apoptosis. Cancer Res 55:2507
82. Strobel T, Tai YT, Korsmeyer S, Cannistra SA (1998) BAD partly reverses paclitaxel resistance in human ovarian cancer cells. Oncogene 17:2419
83. 2-terminal kinase-mediated activation of interleukin-1β converting enzyme/CED-3-like protease during anticancer drug-induced apoptosis. J Biol Chem 272:4631
84. Yamamoto K, Ichijo H, Korsmeyer SJ (1999) BCL-2 phosphorylated and inactivated by an ASK/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol Cell Biol 19:8469
85. Perkins CL, Fang G, Kim CN, Bhalla KN (2000) The role of Apaf-1, caspase-9, and bid proteins in etoposide- or paclitaxel-induced mitochondrial events during apoptosis. Cancer Res 60:1645
86. Friedrich K, Wieder T, Von Haefen C, Radetzki S, Janicke R, Schulze-Osthoff K, Dorken B, Daniel PT (2001) Overexpression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance. Oncogene 20:2749
87. Yang XH, Sladek TL, Liu X, Butler BR, Froelich CJ, Thor AD (2001) Reconstitution of caspase 3 sensitizes MCF-7 breast cancer cells to doxorubicin- and etoposide-induced apoptosis. Cancer Res 61:348
88. Liang Y, Yan C, Schor NF (2001) Apoptosis in the absence of caspase 3. Oncogene 20:6570
89. Kim R, Inoue H, Tanabe K, Toge T (2001) Effect of inhibitors of cysteine and serine proteases in anticancer drug-induced apoptosis in gastric cancer cells. Int J Oncol 18:1227
90. Webb A, Cunningham D, Cotter F, Clarke PA, di Stefano F, Ross P, Corbo M, Dziewanowska Z (1997) BCL-2 anti-sense therapy in patients with non-Hodgkin lymphoma. Lancet 349:1137
91. Jansen B, Wacheck V, Heere-Ress E, Schlagbauer-Wadl H, Hoeller C, Lucas T, Hoermann M, Hollenstein U, Wolff K, Pehamberger H (2000) Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 356:1728
92. Zangermeister-Wittke U, Leech SH, Olie RA, Simoes-Wust AP, Gautschi O, Luedke GH, Natt F, Haner R, Martin P, Hall J, Nalin CM, Stahel RA (2000) A novel bispecific antisense oligonucleotide inhibiting both bcl-2 and bcl-XL expression efficiently induces apoptosis in tumor cells. Clin Cancer Res 6:2547
93. Kim R, Osaki A, Toge T (2001) A pitfall in the survival benefit of adjuvant chemotherapy for node- and hormone receptor-positive patients with breast cancer: The paradoxical role of Bcl-2 oncoprotein. Int J Oncol 19:1075
94. Dong L, Wang W, Wang F, Stoner M, Reed JC, Harigai M, Samudio I, Kladde MP, Vyhlidal C, Safe S (1999) Mechanisms of transcriptional activation of bcl-2 gene expression by 17beta-estradiol in breast cancer cells. J Biol Chem 274:32099
95. Kallio MJ, Nieminen M, Eriksson JE (2001) Human inhibitor of apoptosis protein (IAP) survivin participates in regulation of chromosome segregation and mitotic exit. FASEB J 15:2721
96. Grossman D, Kim PJ, Schechner JS, Altieri DC (2001) Inhibition of melanoma tumor growth in vivo by survivin targeting. Proc Natl Acad Sci U S A 98:635
97. Mesri M, Wall NR, Li J, Kim RW, Altieri DC (2001) Cancer gene therapy using a survivin mutant adenovirus. J Clin Invest 108:981
98. Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH (2000) Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that results in the release of cytochrome c. Cell Death Differ 7:1166
99. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science 292:727
100. Ruffolo SC, Breckenridge DG, Nguyen M, Goping IS, Gross A, Korsmeyer SJ, Li H, Yuan J, Shore GC (2000) BID-dependent and BID-independent pathways for BAX insertion into mitochondria. Cell Death Differ 7:1101
101. Bosanquet AG, Bell PB, Burlton AR, Amos TA (1996) Correlation of bcl-2 with P-glycoprotein expression in chronic lymphocytic leukemia and other hematological neoplasms but of neither marker with ex vivo chemosensitivity or patient survival. Leuk Lymphoma 24:141
102. Kasimir-Bauer S, Ottinger H, Mousors P, Beelen DW, Brittinger G, Seeber S, Scheulen ME (1998) In acute myeloid leukemia, coexpression of at least two proteins, including P-glycoprotein, the multidrug resistance-related protein, bcl-2, mutant p53, and heat-shock protein 27, is predictive of the response to induction chemotherapy. Exp Hematol 26:1111
103. Eid H, Gulyas M, Geczi L, Bodrogi I, Institoris E, Bak M (1998) Expression of bcl-2 in testicular carcinoma: Correlation with tumor progression and MDR1/Pgp. Cancer 83:331
104. Chadderton A, Villeneuve DJ, Gluck S, Kirwan-Rhude AF, Gannon BR, Blais DE, Parissenti AM (2000) Role of specific apoptotic pathways in the restoration of paclitaxel-induced apoptosis by valspodar in doxorubicin-resistant MCF-7 breast cancer cells. Breast Cancer Res Treat 59:231
105. Jazirehi AR, Ng CP, Gan XH, Schiller G, Bonavida B (2001) Adriamycin sensitizes the adriamycin-resistant 8226/Dox40 human multiple myeloma cells to apo2L/tumor necrosis factor-related apoptosis-inducing ligand-mediated (TRAIL) apoptosis. Clin Cancer Res 7:3874
106. Ohi, Y, Kim R, Toge T (2000) Overcoming of multidrug resistance by introducing the apoptosis gene, bcl-Xs, into MRP-overexpressing drug-resistant cells. Int J Oncol 16:959
107. Kim R, Ohi Y, Inoue H, Toge T (1999) Activation and the interaction of proapoptotic genes in modulating sensitivity to anticancer drugs in gastric cancer cells. Int J Oncol 15:751
108. Nabboltz JM, Slamon D (2001) New adjuvant strategies for breast cancer: Meeting the challenge of integrating chemotherapy and trastuzumab (Herceptin). Semin Oncol 28:1
109. Baselga J (2001) The EGFR as a target for anticancer therapy - Focus on cetuximab. Eur J Cancer 37:16
110. Saltz L, Rubin M, Hochster H, Tchekmeydian NS, Waksal H, Needle M (2001) Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11 refractory colorectal cancer (CRC) that express epidermal growth factor receptor (EGFR) (abstract no. 7). Proc ASCO 20:3a
111. Cuello M, Ettenberg SA, Clark AS, Keane MM, Posner RH, Nau MM, Dennis PA, Lipkowitz S (2001) Down-regulation of the erbB-2 receptor by trastuzumab (Herceptin) enhances tumor necrosis-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2. Cancer Res 61:4892
112. Roh H, Pippin JA, Green DW, Boswell CB, Hirose CT, Mokadam N, Drebin JA (2000) HER-2/neu antisense targeting of human breast carcinoma. Oncogene 19:6138
113. Anderson NG, Ahmad T, Chan K, Dobson R, Bundred NJ (2001) ZD1839 (Iressa), a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, potently inhibits the growth of EGFR-positive cancer cell lines with or without erbB2 overexpression. Int J Cancer 94:774
114. Moasser MM, Basso A, Averbuch SD, Rosen N (2001) The tyrosine kinase inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 61:7184
115. Chen HX, Gore-Langton RE, Cheson BD (2001) Clinical trials referral resource: Current clinical trials of the antiVEGF monoclonal antibody bevacizumab. Oncology (Huntingt) 15:1023