Abstract
Expression of Bcl-2 in multiple myeloma is associated with resistance to chemotherapeutic drugs. Conversely, suppression of Bcl-2 enhanced the chemosensitivity of myeloma cells in vitro. G3139 is an antisense oligodeoxynucleotide targeted to the first six codons of the Bcl-2 mRNA open reading frame. In this study, G3139 was delivered as a continuous intravenous infusion for 7 days at a fixed dose of 7 mg/kg/day in combination with VAD (vincristine, adriamycin, and dexamethasone) chemotherapy. In total, 10 heavily pretreated patients with refractory myeloma participated in this trial, including eight patients with VAD refractory disease. The combination of G3139 and VAD was feasible and well tolerated. Seven patients (70%) responded including four patients (40%) with a partial response and three patients (30%) with a minor response. Median progression-free survival was 6 months (range, 2–7+ months) and median overall survival has not been reached. G3139 downregulated Bcl-2 protein levels in peripheral blood circulating myeloma cells, B cells, T cells, and monocytes. These results indicate that G3139 may overcome classical resistance and restore sensitivity of myeloma tumor cells to VAD chemotherapy.
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References
Moalli PA, Pillay S, Weiner D, Leikin R, Rosen ST . A mechanism of resistance to glucocorticoids in multiple myeloma: transient expression of a truncated glucocorticoid receptor mRNA. Blood 1992; 79: 213–222.
Ishikawa H, Kawano MM, Okada K, Tanaka H, Tanabe O, Sakai A et al. Expressions of DNA topoisomerase I and II gene and the genes possibly related to drug resistance in human myeloma cells. Br J Haematol 1993; 83: 68–74.
Krett NL, Pillay S, Moalli PA, Greipp PR, Rosen ST . A variant glucocorticoid receptor messenger RNA is expressed in multiple myeloma patients. Cancer Res 1995; 55: 2727–2729.
Valkov NI, Sullivan DM . Drug resistance to DNA topoisomerase I and II inhibitors in human leukemia, lymphoma, and multiple myeloma. Semin Hematol 1997; 34 (4 Suppl 5): 48–62.
Linsenmeyer ME, Jefferson S, Wolf M, Matthews JP, Board PG, Woodcock DM . Levels of expression of the mdr1 gene and glutathione S-transferase genes 2 and 3 and response to chemotherapy in multiple myeloma. Br J Cancer 1992; 65: 471–475.
Dalton WS, Grogan TM, Meltzer PS, Scheper RJ, Durie BG, Taylor CW et al. Drug-resistance in multiple myeloma and non-Hodgkin's lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy. J Clin Oncol 1989; 7: 415–424.
Epstein J, Xiao HQ, Oba BK . P-glycoprotein expression in plasma-cell myeloma is associated with resistance to VAD. Blood 1989; 74: 913–917.
Sonneveld P, Durie BG, Lokhorst HM, Marie JP, Solbu G, Suciu S et al. Modulation of multidrug-resistant multiple myeloma by cyclosporin. The Leukaemia Group of the EORTC and the HOVON. Lancet 1992; 340: 255–259.
Grogan TM, Spier CM, Salmon SE, Matzner M, Rybski J, Weinstein RS et al. P-glycoprotein expression in human plasma cell myeloma: correlation with prior chemotherapy. Blood 1993; 81: 490–495.
Raaijmakers HG, Izquierdo MA, Lokhorst HM, de Leeuw C, Belien JA, Bloem AC et al. Lung-resistance-related protein expression is a negative predictive factor for response to conventional low but not to intensified dose alkylating chemotherapy in multiple myeloma. Blood 1998; 91: 1029–1036.
Filipits M, Drach J, Pohl G, Schuster J, Stranzl T, Ackermann J et al. Expression of the lung resistance protein predicts poor outcome in patients with multiple myeloma. Clin Cancer Res 1999; 5: 2426–2430.
Spanswick VJ, Craddock C, Sekhar M, Mahendra P, Shankaranarayana P, Hughes RG et al. Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma. Blood 2002; 100: 224–229.
Solary E, Droin N, Bettaieb A, Corcos L, Dimanche-Boitrel MT, Garrido C . Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies. Leukemia 2000; 14: 1833–1849.
O'Gorman DM, Cotter TG . Molecular signals in anti-apoptotic survival pathways. Leukemia 2001; 15: 21–34.
Johnstone RW, Ruefli AA, Lowe SW . Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002; 108: 153–164.
Hamilton MS, Barker HF, Ball J, Drew M, Abbot SD, Franklin IM . Normal and neoplastic human plasma cells express bcl-2 antigen. Leukemia 1991; 5: 768–771.
Pettersson M, Jernberg-Wiklund H, Larsson LG, Sundstrom C, Givol I, Tsujimoto Y et al. Expression of the bcl-2 gene in human multiple myeloma cell lines and normal plasma cells. Blood 1992; 79: 495–502.
Sangfelt O, Osterborg A, Grander D, Anderbring E, Ost A, Mellstedt H et al. Response to interferon therapy in patients with multiple myeloma correlates with expression of the Bcl-2 oncoprotein. Int J Cancer 1995; 63: 190–192.
Ong F, van Nieuwkoop JA, Groot-Swings GM, Hermans J, Harvey MS, Kluin PM et al. Bcl-2 protein expression is not related to short survival in multiple myeloma. Leukemia 1995; 9: 1282–1284.
Harada N, Hata H, Yoshida M, Soniki T, Nagasaki A, Kuribayashi N et al. Expression of Bcl-2 family of proteins in fresh myeloma cells. Leukemia 1998; 12: 1817–1820.
Puthier D, Pellat-Deceunynck C, Barille S, Robillard N, Rapp MJ, Juge-Morineau N et al. Differential expression of Bcl-2 in human plasma cell disorders according to proliferation status and malignancy. Leukemia 1999; 13: 289–294.
Renner S, Weisz J, Krajewski S, Krajewska M, Reed JC, Lichtenstein A . Expression of BAX in plasma cell dyscrasias. Clin Cancer Res 2000; 6: 2371–2380.
Gross A, McDonnell JM, Korsmeyer SJ . BCL-2 family members and the mitochondria in apoptosis. Genes Dev 1999; 13: 1899–1911.
Kroemer G, Reed JC . Mitochondrial control of cell death. Nat Med 2000; 6: 513–519.
Adrain C, Creagh EM, Martin SJ . Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2. EMBO J 2001; 20: 6627–6636.
Debatin KM, Poncet D, Kroemer G . Chemotherapy: targeting the mitochondrial cell death pathway. Oncogene 2002; 21: 8786–8803.
McDonnell TJ, Korsmeyer SJ . Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature 1991; 349: 254–256.
Strasser A, Harris AW, Cory S . E mu-bcl-2 transgene facilitates spontaneous transformation of early pre-B and immunoglobulin-secreting cells but not T cells. Oncogene 1993; 8: 1–9.
Tu Y, Xu FH, Liu J, Vescio R, Berenson J, Fady C, Lichtenstein A . Upregulated expression of BCL-2 in multiple myeloma cells induced by exposure to doxorubicin, etoposide, and hydrogen peroxide. Blood 1996; 88: 1805–1812.
Gazitt Y, Fey V, Thomas C, Alvarez R . Bcl-2 overexpression is associated with resistance to dexamethasone, but not melphalan, in multiple myeloma cells. Int J Oncol 1998; 13: 397–405.
Derenne S, Monia B, Dean NM, Taylor JK, Rapp MJ, Harousseau JL et al. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. Blood 2002; 100: 194–199.
van de Donk NW, Kamphuis MM, Van Dijk M, Borst HP, Bloem AC, Lokhorst HM . Chemosensitization of myeloma plasma cells by an antisense-mediated downregulation of Bcl-2 protein. Leukemia 2003; 17: 211–219.
Liu Q, Gazitt Y . Potentiation of dexamethasone-, paclitaxel-, and Ad-p53-induced apoptosis by Bcl-2 antisense oligodeoxynucleotides in drug-resistant multiple myeloma cells. Blood 2003; 101: 4105–4114.
Webb A, Cunningham D, Cotter F, Clarke PA, di Stefano F, Ross P et al. BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet 1997; 349: 1137–1141.
Waters JS, Webb A, Cunningham D, Clarke PA, Raynaud F, di Stefano F et al. Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma. J Clin Oncol 2000; 18: 1812–1823.
Rai KR, O'Brien S, Cunningham C, Turkina AG, Ochoa L, Frankel SR . Genasense (Bcl-2 Antisense) monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia: Phase 1 and 2 results. Blood 2002; 100: 384a.
Jansen B, Wacheck V, Heere-Ress E, Schlagbauer-Wadl H, Hoeller C, Lucas T et al. Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 2000; 356: 1728–1733.
Rudin CM, Otterson GA, Mauer AM, Villalona-Calero MA, Tomek R, Prange B 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.
Chi KN, Gleave ME, Klasa R, Murray N, Bryce C, Lopes de Menezes DE 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.
Ochoa L, Kuhn J, Salinas R, Hammond L, Hao D, Denis L . A phase I, pharmacokinetic, and biologic correlative study of G3139 and irinotecan (CPT-11) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 2001; 20: 75a.
Marcucci G, Byrd JC, Dai G, Klisovic MI, Kourlas PJ, Young DC 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: 425–432.
Klasa RJ, Gillum AM, Klem RE, Frankel SR . Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev 2002; 12: 193–213.
Segeren CM, Sonneveld P, van der HB, Baars JW, Biesma DH, Cornellissen JJ et al. Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol 1999; 105: 127–130.
Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998; 102: 1115–1123.
Boersma-Vreugdenhil GR, Peeters T, Bast BJ . Translocation of the IgH locus is nearly ubiquitous in multiple myeloma as detected by immuno-FISH. Blood 2003; 101: 1653.
Blade J, Esteve J . Treatment approaches for relapsing and refractory multiple myeloma. Acta Oncol 2000; 39: 843–847.
Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002; 100: 3063–3067.
Bishop MR, Iversen PL, Bayever E, Sharp JG, Greiner TC, Copple BL et al. Phase I trial of an antisense oligonucleotide OL(1)p53 in hematologic malignancies. J Clin Oncol 1996; 14: 1320–1326.
Glover JM, Leeds JM, Mant TG, Amin D, Kisner DL, Zuckerman JE et al. Phase I safety and pharmacokinetic profile of an intercellular adhesion molecule-1 antisense oligodeoxynucleotide (ISIS 2302). J Pharmacol Exp Ther 1997; 282: 1173–1180.
Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ . Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 1993; 75: 229–240.
Acknowledgements
This study was financially supported by a grant from the Dutch Cancer Society (KWF). One of the authors (S.R.F.) is employed by a company (Genta) whose product was studied in the present work.
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van de Donk, N., de Weerdt, O., Veth, G. et al. G3139, a Bcl-2 antisense oligodeoxynucleotide, induces clinical responses in VAD refractory myeloma. Leukemia 18, 1078–1084 (2004). https://doi.org/10.1038/sj.leu.2403363
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DOI: https://doi.org/10.1038/sj.leu.2403363
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