Targeting the Bcl-2

Current Opinion in Oncology

Volumn 21, Issue 6, 2009, Pages 516-523

  Patel, Mehul R ^a   Masood, Aisha ^b   Patel, Priya S ^a   Chanan Khan, Asher A ^a  

^a ROSWELL PARK CANCER INSTITUTE   (United States)

^b HACKENSACK UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

Apoptosis; Bcl 2; Small molecule inhibitors

Indexed keywords

4 [4 (4' CHLORO 2 BIPHENYLYLMETHYL) 1 PIPERAZINYL] N [4 [3 DIMETHYLAMINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 NITROBENZENESULFONYL]BENZAMIDE; 4 [4 [2 (4 CHLOROPHENYL) 5,5 DIMETHYL 1 CYCLOHEXEN 1 YLMETHYL] 1 PIPERAZINYL] N [4 [3 MORPHOLINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 (TRIFLUOROMETHYLSULFONYL)BENZENESULFONYL]BENZAMIDE; ALPHA INTERFERON; ANTISENSE OLIGONUCLEOTIDE; BENDAMUSTINE; CARBOPLATIN; CISPLATIN; CYCLOPHOSPHAMIDE; CYTARABINE; DACARBAZINE; DAUNORUBICIN; DEXAMETHASONE; DOCETAXEL; DOXORUBICIN; ETOPOSIDE; FLUDARABINE; FLUOROURACIL; GEMTUZUMAB OZOGAMICIN; IRINOTECAN; ISOSORBIDE; MITOXANTRONE; OBATOCLAX; OBLIMERSEN; PREDNISONE; PROTEIN BCL 2; RITUXIMAB; THALIDOMIDE; TOPOTECAN; VINCRISTINE; ANTINEOPLASTIC AGENT; COMPLEMENTARY DNA;

ACUTE GRANULOCYTIC LEUKEMIA; ANTISENSE THERAPY; ASTHENIA; BREAST CANCER; CANCER COMBINATION CHEMOTHERAPY; CANCER SURVIVAL; CHRONIC LYMPHATIC LEUKEMIA; CLINICAL TRIAL; COLORECTAL CANCER; CONTINUOUS INFUSION; CYTOKINE RELEASE SYNDROME; DRUG FEVER; DRUG MECHANISM; DRUG MEGADOSE; DRUG TARGETING; ESOPHAGUS CANCER; FATIGUE; FOLLICULAR LYMPHOMA; GLIOBLASTOMA; HUMAN; HYPOTENSION; ILEUS; IMMUNOPATHOLOGY; KIDNEY CARCINOMA; LUNG SMALL CELL CANCER; LYMPHOMA; MELANOMA; METASTASIS; MULTIPLE MYELOMA; NEUTROPENIA; NONHODGKIN LYMPHOMA; OVERALL SURVIVAL; PRIORITY JOURNAL; PROSTATE CANCER; QT PROLONGATION; REVIEW; RIGOR; SOLID TUMOR; STOMACH CANCER; THROMBOCYTOPENIA; TREATMENT OUTCOME; APOPTOSIS; DRUG ANTAGONISM; DRUG EFFECT; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; NEOPLASM; PHYSIOLOGY;

ANTINEOPLASTIC AGENTS; APOPTOSIS; DNA, ANTISENSE; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; NEOPLASMS; PROTO-ONCOGENE PROTEINS C-BCL-2; TREATMENT OUTCOME;

EID: 74049092271     PISSN: 10408746     EISSN: None     Source Type: Journal    
DOI: 10.1097/CCO.0b013e328331a7a4     Document Type: Review

References (91)

1. Hunter AM, LaCasse EC, Korneluk RG. The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 2007; 12:1543-1568.
2. Ikegaki N, Katsumata M, Minna J, et al. Expression of bcl-2 in small cell lung carcinoma cells. Cancer Res 1994; 54:6-8. (Pubitemid 24042076)
3. Jiang SX, Sato Y, Kuwao S, et al. Expression of bcl-2 oncogene protein is prevalent In small cell lung carcinomas. J Pathol 1995; 177:135-138.
4. Lee KH, Im SA, Oh DY, et al. Prognostic significance of bcl-2 expression in stage III breast cancer patients who had received doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy. BMC Cancer 2007; 7:63.
5. Khor LY, Moughan J, Al-Saleem T, et al. Bcl-2 and Bax expression predict prostate cancer outcome in men treated with androgen deprivation and radiotherapy on radiation therapy oncology group protocol 92-02. Clin Cancer Res 2007; 13:3585-3590. (Pubitemid 46955119)
6. Contu PC, Contu SS, Moreira LF. Bcl-2 expression in rectal cancer. Arq Gastroenterol 2006; 43:284-287.
7. Bakhshi A, Jensen JP, Goldman P, et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 1985; 41:899-906. (Pubitemid 15243395)
8. Tsujimoto Y, Yunis J, Onorato-Showe L, et al. Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chromosome translocation. Science 1984; 224:1403-1406. (Pubitemid 14123338)
9. Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008; 9:47-59.
10. Skommer J, Wlodkowic D, Deptala A. Larger than life: mitochondria and the Bcl-2 family. Leuk Res 2007; 31:277-286. (Pubitemid 46073182)
11. Campos L, Rouault JP, Sabido O, et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 1993; 81:3091-3096. (Pubitemid 23162130)
12. Miyashita T, Reed JC. bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res 1992; 52:5407-5411.
13. Walton Ml, Whysong D, O'Connor PM, et al. Constitutive expression of human Bcl-2 modulates nitrogen mustard and camptothecin induced apoptosis. Cancer Res 1993; 53:1853-1861. (Pubitemid 23127114)
14. Dole M, Nunez G, Merchant AK, et al. Bcl-2 inhibits chemotherapy-induced apoptosis In neuroblastoma. Cancer Res 1994; 54:3253-3259. (Pubitemid 24208938)
15. Reed JC, Stein C, Subasinghe C, et al. Antisense-mediated inhibition of BCL2 protooncogene expression and leukemic cell growth and survival: comparisons of phosphodiester and phosphorothioate oligodeoxynucleotides. Cancer Res 1990; 50:6565-6570. (Pubitemid 20348780)
16. Ziegler A, Luedke GH, Fabbro D, et al. Induction of apoptosis in small-cell lung cancer cells by an antisense oligodeoxynucleotide targeting the Bcl-2 coding sequence. J Natl Cancer Inst 1997; 89:1027-1036. (Pubitemid 27327867)
17. van de Donk NW, Kamphuis MM, van Dijk M, et al. Chemosensitization of myeloma plasma cells by an antisense-mediated downregulation of Bcl-2 protein. Leukemia 2003; 17:211-219. (Pubitemid 36175908)
18. Jansen B, Schlagbauer-Wadl H, Brown BD, et al. bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nat Med 1998; 4:232234. (Pubitemid 28137379)
19. Lacy J, Loomis R, Grill S, et al. Systemic Bcl-2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV - nasopharyngeal carcinoma xenografts in SCID mice. Int J Cancer 2006; 119:309-316. (Pubitemid 43911895)
20. Smith MR, Abubakr Y, Mohammad R, et al. Antisense oligodeoxyribonucleotide down-regulation of bcl-2 gene expression in hibits growth of the low-grade non-Hodgkin's lymphoma cell line WSU-FSCCL. Cancer Gene Ther 1995; 2:207-212.
21. Cotter FE, Johnson P, Hall P, et al. Antisense oligonucleotides suppress B-cell lymphoma growth In a SCID-hu mouse model. Oncogene 1994; 9:30493055. (Pubitemid 24296785)
22. De Cesare M, Perego P, Righetti SC, et al. Enhanced antitumour efficacy of gimatecan in combination with Bcl-2 antisense oligonucleotide in human melanoma xenografts. Eur J Cancer 2005; 41:1213-1222. (Pubitemid 40725581)
23. 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. (Pubitemid 30082226)
24. Zangemeister-Wittke U, Schenker T, Luedke GH, et al. Synergistic cytotoxicity of bcl-2 antisense oligodeoxynucleotides and etoposide, doxorubicin and cisplatin on small-cell lung cancer cell lines. Br J Cancer 1998; 78:10351042. (Pubitemid 28463979)
25. Leung S, Miyake H, Zellweger T, et al. Synergistic chemosensitization and inhibition of progression to androgen independence by antisense Bcl-2 oligodeoxynucleotide and paclitaxel in the LNCaP prostate tumor model. Int J Cancer 2001; 91:846-850. (Pubitemid 32178655)
26. Klasa RJ, Gillum AM, Klem RE, et al. Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev 2002; 12:193-213.
27. Klasa RJ, Bally MB, Ng R, et al. Eradication of human non-Hodgkin's lymphoma in SCID mice by BCL-2 antisense oligonucleotides combined with low-dose cyclophosphamide. Clin Cancer Res 2000; 6:2492-2500. (Pubitemid 30399220)
28. Dias N, Stein CA. Antisense oligonucleotides: basic concepts and mechanisms. Mol Cancer Ther 2002; 1:347-355.
29. Waters JS, Webb A, Cunningham D, et al. Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy In patients with nonHodgkin's lymphoma. J Clin Oncol 2000; 18:1812-1823. (Pubitemid 30261918)
30. Morris MJ, Tong WP, Cordon-Cardo C, et al. Phase I trial of BCL-2 antisense oligonucleotide (G3139) administered by continuous intravenous infusion in patients with advanced cancer. Clin Cancer Res 2002; 8:679-683.
31. O'Brien SM, Cunningham CC, Golenkov AK, et al. Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia. J Clin Oncol 2005; 23:76977702.
32. O'Brien S, Moore JO, Boyd TE, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) In patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2007; 25:1114-1120.
33. Marcucci G, Byrd JC, Dai G, et al. Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood 2003; 101:425432.
34. Moore JO, Seiter K, Kolitz JE, et al. Phase 2 study of oblimersen sodium (G3139; Bcl-2 antisense; genasense(R)) plus gemtuzumab ozogamcin (Mylotarg(R)) In elderly patients with relapsed acute myeloid leukemia (AML). Blood (ASH Annual Meeting Abstracts) 2004; 104:865.
35. Marcucci G, Stock W, Dai G, et al. Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity. J Clin Oncol 2005; 23:3404-3411. (Pubitemid 46249698)
36. Marcucci G, Moser B, Blum W, et al. A phase III randomized trial of intensive induction and consolidation chemotherapy (-/-) oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients >60 years old. ASCO Meeting Abstracts 2007; 25:7012.
37. van de Donk NW, de Weerdt O, Veth G, et al. G3139, a Bcl-2 antisense oligodeoxynucleotide, induces clinical responses in VAD refractory myeloma. Leukemia 2004; 18:1078-1084.
38. Badros AZ, Goloubeva O, Rapoport AP, et al. Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide In relapsed multiple myeloma patients. J Clin Oncol 2005; 23:4089-4099. (Pubitemid 46211314)
39. Chanan-Khan AA, Niesvizky R, Hohl RJ, et al. Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leuk Lymphoma 2009; 50:559-565.
40. Jansen B, Wacheck V, Heere-Ress E, et al. Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 2000; 356:17281733. (Pubitemid 30948874)
41. Bedikian AY, Millward M, Pehamberger H, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 2006; 24:4738-4745. (Pubitemid 46630937)
42. Rudin CM, Otterson GA, Mauer AM, et al. A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer. Ann Oncol 2002; 13:539-545.
43. Rudin CM, Kozloff M, Hoffman PC, et al. Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. J Clin Oncol 2004; 22:1110-1117. (Pubitemid 41095045)
44. Rudin CM, Salgia R, Wang X, et al. Randomized phase II study of carboplatin and etoposide with or without the bcl-2 antisense oligonucleotide oblimersen for extensive-stage small-cell lung cancer: CALGB 30103. J Clin Oncol 2008; 26:870-876.
45. Chi KN, Gleave ME, Klasa R, et al. A phase I dose-finding study of combined treatment with an antisense Bcl-2 oligonucleotide (Genasense) and mitoxantrone in patients with metastatic hormone-refractory prostate cancer. Clin Cancer Res 2001; 7:3920-3927.
46. Tolcher AW, Kuhn J, Schwartz G, et al. A phase I pharmacokinetic and biological correlative study of oblimersen sodium (genasense, g3139), an antisense oligonucleotide to the bcl-2 mRNA, and of docetaxel in patients with hormone-refractory prostate cancer. Clin Cancer Res 2004; 10:50485057.
47. Tolcher AW, Chi K, Kuhn J, et al. A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormone-refractory prostate cancer. Clin Cancer Res 2005; 11:38543861.
48. Sternberg CN, Dumez H, Van Poppel H, et al. Docetaxel plus oblimersen sodium (Bcl-2 antisense oligonucleotide): an EORTC multicenter, randomized phase II study In patients with castration-resistant prostate cancer. Ann Oncol 2009; 20:1264-1269.
49. Moulder SL, Symmans WF, Booser DJ, et al. Phase I/II study of G3139 (Bcl-2 antisense oligonucleotide) in combination with doxorubicin and docetaxel in breast cancer. Clin Cancer Res 2008; 14:7909-7916.
50. Margolin K, Synold TW, Lara P, et al. Oblimersen and alpha-interferon in metastatic renal cancer: a phase II study of the California Cancer Consortium. J Cancer Res Clin Oncol 2007; 133:705-711. (Pubitemid 47319237)
51. Mita MM, Ochoa L, Rowinsky EK, et al. A phase I, pharmacokinetic and biologic correlative study of oblimersen sodium (Genasense, G3139) and irinotecan in patients with metastatic colorectal cancer. Ann Oncol 2006; 17:313-321.
52. Kaubisch A, Wu Y-H, Wadler S. Phase I/II study of genasense (G3139) in combination with cisplatin (Cis) and fluorouracil (FU) in patients with advanced esophageal, gastro-esophageal junction and gastric cancer (P5385). ASCO Meeting Abstracts 2005; 23:9695.
53. Zeitlin BD, Zeitlin IJ, Nor JE. Expanding circle of inhibition: small-molecule inhibitors of Bcl-2 as anticancer cell and antianglogenic agents. J Clin Oncol 2008; 26:4180-4188.
54. Dodou K, Anderson RJ, Small DA, et al. Investigations on gossypol: past and present developments. Expert Opin Invest Drugs 2005; 14:14191434. (Pubitemid 41601456)
55. Wolter KG, Wang SJ, Henson BS, et al. (-)-Gossypol inhibits growth and promotes apoptosis of human head and neck squamous cell carcinoma in vivo. Neoplasia 2006; 8:163-172.
56. Mohammad RM, Wang S, Aboukameel A, et al. Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-X(L) [(-)-gossypol] against diffuse large cell lymphoma. Mol Cancer Ther 2005; 4:13-21.
57. Xu L, Yang D, Wang S, et al. (-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer. Mol Cancer Ther 2005; 4:197-205. (Pubitemid 40340199)
58. Bauer JA, Trask DK, Kumar B, et al. Reversal of cisplatin resistance with a BH3 mimetic, (.).gossypol, in head and neck cancer cells: role of wild-type p53 and Bcl-xL Mol Cancer Ther 2005; 4:1096-1104.
59. Stein RC, Joseph AE, Matlin SA, et al. A preliminary clinical study of gossypol In advanced human cancer. Cancer Chemother Pharmacol 1992; 30:480482.
60. Flack MR, Pyle RG, Mullen NM, et al. Oral gossypol in the treatment of metastatic adrenal cancer. J Clin Endocrinol Metab 1993; 76:10191024.
61. Bushunow P, Reidenberg MM, Wasenko J, et al. Gossypol treatment of recurrent adult malignant gliomas. J Neurooncol 1999; 43:79-86. (Pubitemid 29351981)
62. Van Poznak C, Seidman AD, Reidenberg MM, et al. Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial. Breast Cancer Res Treat 2001 ; 66:239-248. (Pubitemid 32675026)
63. James DF, Prada CE, Castro JE, et al. AT 101, an inhibitor of Bcl-2 family members is cytotoxic to a heterogeneous group of CLL samples and synergistic with rituximab. Blood (ASH Annual Meeting Abstracts) 2005; 106:2979.
64. James DF, Castro JE, Loria O, et al. AT-101, a small molecule Bcl-2 antagonist, in treatment naive CLL patients (pts) with high risk features: preliminary results from an ongoing phase I trial. ASCO Meeting Abstracts 2006; 24:6605.
65. Castro JE, Loria OJ, Aguillon RA, et al. A phase II, open label study of AT-101 in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Evaluation of two dose regimens. Blood (ASH Annual Meeting Abstracts) 2007; 110:3119.
66. Castro JE, Olivier LJ, Robier AA, et al. A phase II, open label study of AT-101 in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts) 2006; 108:2838.
67. Kingsley E, Richards D, Garbo L, et al. An open-label, multicenter, phase II study of AT-101 in combination with rituximab (R) in patients with untreated, grade 1 -2, follicular non-Hodgkin's lymphoma (FL). ASCO Meeting Abstracts 2009; 27:8582.
68. Liu G, Kelly WK, Wilding G, et al. An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin Cancer Res 2009; 15:3172-3176.
69. MacVicar GR, Greco A, Reeves J, et al. An open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with castrate-resistant prostate cancer (CRPC). ASCO Meeting Abstracts 2009; 27:5062.
70. Poiesz B, Reeves J, McNulty W, et al. Preliminary report of an open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with docetaxel refractory prostate cancer. ASCO Meeting Abstracts 2009; 27:5145.
71. Leal TB, Schelman W, Traynor A, et al. A phase I study of R-(-)-gossypol (AT101) in combination with cisplatin (P) and etoposide (E) in patients with advanced solid tumors and extensive-stage small cell lung cancer (ESSCLC). ASCO Meeting Abstracts 2009; 27:e13502.
72. Heist RS, Fain J, Chinnasami B, et al. A phase I/II (P1 /P2) study of AT-101 in combination with topotecan (T) in patients with relapsed or refractory small cell lung cancer (SCLC) after prior platinum-containing first-line chemotherapy. ASCO Meeting Abstracts 2009; 27:8106.
73. Fiveash JB, Chowdhary SA, Peereboom D Jr, et al. NABTT-0702: a phase II study of R-(-)-gossypol (AT-101) in recurrent glioblastoma multiforme (GBM). ASCO Meeting Abstracts 2009; 27:2010.
74. Contractor R, Konopleva M, Samudlo I, et al. Inhibition of Bcl-2 signaling by small molecule BH3 inhibitor GX15-070 as a novel therapeutic strategy in AML. Blood (ASH Annual Meeting Abstracts) 2005; 106:3372.
75. Watt JC, Konopleva M, Contractor R, et al. Inhibition of Bcl-2 signaling by small molecule BH3 inhibitor GX15-070 as a novel therapeutic strategy in AML Blood (ASH Annual Meeting Abstracts) 2006; 108:2584.
76. WeI Y, Kadia T, Tong W, et al. The combination of a histone deacetylase (HDAC) inhibitor with the BCL-2 inhibitor GX15-070 has synergistic antileukemia effect by inducing both apoptotic and autophagic pathways. Blood (ASH Annual Meeting Abstracts) 2008; 112:1633.
77. O'Brien SM, Claxton DF, Crump M, et al. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood 2009; 113:299-305.
78. Schimmer AD, Brandwein J, O'Brien SM, et al. A phase I trial of the small molecule Pan-Bcl-2 family inhibitor obatoclax mesylate (GX15-070) administered by continuous infusion for up to four days to patients with hematological malignancies. Blood (ASH Annual Meeting Abstracts) 2007; 110:892.
79. Borthakur G, O'Brien S, Ravandi-Kashani F, et al. A phase I trial of the small molecule Pan-Bcl-2 family inhibitor obatoclax mesylate (GX15-070) administered by 24 hour infusion every 2 weeks to patients with myeloid malignancies and chronic lymphocytic leukemia (CLL). Blood (ASH Annual Meeting Abstracts) 2006; 108:2654.
80. Firozvi K, Hwang J, Hansen N, et al. A phase I study of the pan-Bcl2 family inhibitor GX15-070, administered as a 3-h weekly infusion in patients with refractory solid tumors or lymphomas. ASCO Meeting Abstracts 2006; 24:3081.
81. Raza A, Galili N, Borthakur G, et al. A safety and schedule seeking trial of Bcl-2 inhibitor obatoclax In previously untreated older patients with acute myeloid leukemia (AML). ASCO Meeting Abstracts 2009; 27:3579.
82. Verstovsek S, Raza A, Schimmer AD, et al. A phase II trial of the small molecule Pan-Bcl-2 family inhibitor obatoclax mesylate (GX15-070) administered by a 24-h continuous infusion every 2 weeks to patients with chronic idiopathic myelofibrosis (CIMF). Blood (ASH Annual Meeting Abstracts) 2007; 110:3553.
83. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435:677681.
84. Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006; 10:375-388.
85. Kuroda J, Puthalakath H, Cragg MS, et al. Bim and Bad mediate imatinibinduced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss Is overcome by a BH3 mimetic. Proc Natl Acad Sci U S A 2006; 103:1490714912. (Pubitemid 44527827)
86. Del Gaizo Moore V, Schlis KD, Sallan SE, et al. BCL-2 dependence and ABT737 sensitivity in acute lymphoblastic leukemia. Blood 2008; 111:23002309.
87. Paoluzzi L, Gonen M, Bhagat G, et al. The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies. Blood 2008; 112:2906-2916.
88. Micha D, Cummings J, Shoemaker A, et al. Circulating biomarkers of cell death after treatment with the BH-3 mimetic ABT-737 in a preclinical model of small-cell lung cancer. Clin Cancer Res 2008; 14:7304-7310.
89. Chen S, Dai Y, Harada H, et al. Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res 2007; 67:782-791. (Pubitemid 46192219)
90. Wilson W, O'Connor OO, Roberts AW, et al. ABT-263 activity and safety in patirnts with relapsed or refractory lymphoid malignancies in particular chronic lymphocytic leukrmia (CLL)/small lymphocytic lymphoma (SLL). ASCO Meeting Abstracts 2009; 27:8574.
91. Roberts AW, Wilson W, Gandhi L, et al. Ongoing phase I studies of ABT-263: mitigating Bcl-XL induced thrombocytopenia with lead-in and continuous dosing. ASCO Meeting Abstracts 2009; 27:3505.