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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Miyashita, T. Articles by Reed, J. C. Search for Related Content PubMed PubMed Citation Articles by Miyashita, T. Articles by Reed, J. C. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line T Miyashita and JC Reed La Jolla Cancer Research Foundation, Cancer Research Institute, CA 92037. Previous studies have shown that the bcl-2 gene encodes a mitochondrial protein that contributes to neoplastic cell expansion primarily by promoting cell survival through interference with "programmed cell death" (PCD), also termed "apoptosis." Because many chemotherapeutic drugs are capable of initiating pathways leading to apoptosis, we determined whether deregulated bcl-2 expression could render cells resistant to several drugs commonly used in the treatment of non- Hodgkin's lymphomas, including dexamethasone (DEX), methotrexate (MTX), 1-beta-D-arabinofuranosyl-cytosine (Ara-C), etoposide (VP-16), vincristine (VC), cisplatin (CP), and hydroperoxycyclophosphamide (4- HC). For these experiments, we achieved high levels of p26-Bcl-2 protein production in a human pre-B-cell leukemia line 697 by stable infection with a recombinant bcl-2-containing retrovirus and then compared these cells with control virus-infected 697 cells. Control 697 cells were induced to undergo apoptosis by all drugs tested as defined by DNA degradation into oligonucleosomal-length fragments, cell shrinkage, and subsequent cell death. In contrast, 697 cells with elevated Bcl-2 protein levels exhibited strikingly prolonged cell survival and markedly reduced DNA fragmentation when cultured in the presence of these antineoplastic agents. Although high levels of Bcl-2 protein protected 697 cells from the acute cytotoxic effects of DEX and the other drugs tested, Bcl-2 did not prevent these drugs from suppressing the proliferation of 697 cells. However, when 697 cells were treated with DEX or MTX for 3 days, then washed and cultured in semisolid media without drugs, bcl-2-virus-infected cells gave rise to colonies at much higher frequencies than 697 cells stably infected with control virus. These results indicate that by protecting 697 leukemic cells from the acute cytotoxicity of DEX and some other chemotherapeutic drugs, high levels of p26-Bcl-2 can create the opportunity for re-initiation of cell growth when drugs are withdrawn. The findings may be relevant to clinical correlative studies of non- Hodgkin's lymphoma patients that have found an association between worse prognosis and bcl-2 gene rearrangements or t[14;18] translocations. Volume 81, Issue 1, pp. 151-157, 01/01/1993 Copyright © 1993 by The American Society of Hematology CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Rom, G. von Minckwitz, F. Marme, B. Ataseven, D. Kozian, M. Sievert, B. Schlehe, F. Schuetz, A. Scharf, M. Kaufmann, et al. Phase I study of apoptosis gene modulation with oblimersen within preoperative chemotherapy in patients with primary breast cancer Ann. Onc., July 15, 2009; (2009) mdp208v1. 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Cytochem., February 1, 1999; 47(2): 139 - 150. [Abstract] [Full Text] R. W. Johnstone, E. Cretney, and M. J. Smyth P-Glycoprotein Protects Leukemia Cells Against Caspase-Dependent, but not Caspase-Independent, Cell Death Blood, February 1, 1999; 93(3): 1075 - 1085. [Abstract] [Full Text] [PDF] P. Polverini and J.E. Nor Apoptosis and Predisposition To Oral Cancer Critical Reviews in Oral Biology & Medicine, January 1, 1999; 10(2): 139 - 152. [Abstract] [Full Text] [PDF] J. L. Kenney, M. E. Guinness, T. Curiel, and J. Lacy Antisense to the Epstein-Barr Virus (EBV)-Encoded Latent Membrane Protein 1 (LMP-1) Suppresses LMP-1 and Bcl-2 Expression and Promotes Apoptosis in EBV-Immortalized B Cells Blood, September 1, 1998; 92(5): 1721 - 1727. [Abstract] [Full Text] [PDF] M. Nishikawa, K. Takeda, E. F. Sato, T. Kuroki, and M. Inoue Nitric oxide regulates energy metabolism and Bcl-2 expression in intestinal epithelial cells Am J Physiol Gastrointest Liver Physiol, May 1, 1998; 274(5): G797 - G801. [Abstract] [Full Text] [PDF] J. L. Slack and M. Yu Constitutive Expression of the Promyelocytic Leukemia-Associated Oncogene PML-RARalpha in TF1 Cells: Isoform-Specific and Retinoic Acid-Dependent Effects on Growth, bcl-2 Expression, and Apoptosis Blood, May 1, 1998; 91(9): 3347 - 3356. [Abstract] [Full Text] [PDF] U. Consoli, I. El-Tounsi, A. Sandoval, V. Snell, H.-D. Kleine, W. Brown, J. R. Robinson, F. DiRaimondo, W. Plunkett, and M. Andreeff Differential Induction of Apoptosis by Fludarabine Monophosphate in Leukemic B and Normal T Cells in Chronic Lymphocytic Leukemia Blood, March 1, 1998; 91(5): 1742 - 1748. [Abstract] [Full Text] [PDF] S. H. Kaufmann, J. E. Karp, P. A. Svingen, S. Krajewski, P. J. Burke, S. D. Gore, and J. C. Reed Elevated Expression of the Apoptotic Regulator Mcl-1 at the Time of Leukemic Relapse Blood, February 1, 1998; 91(3): 991 - 1000. [Abstract] [Full Text] [PDF] D. S. Siegel, X. Zhang, R. Feinman, T. Teitz, A. Zelenetz, V. M. Richon, R. A. Rifkind, P. A. Marks, and J. Michaeli Hexamethylene bisacetamide induces programmed cell death (apoptosis) and down-regulates BCL-2 expression in human myeloma cells PNAS, January 6, 1998; 95(1): 162 - 166. [Abstract] [Full Text] [PDF] L. M. Martins, P. W. Mesner, T. J. Kottke, G. S. Basi, S. Sinha, J. S. Tung, P. A. Svingen, B. J. Madden, A. Takahashi, D. J. McCormick, et al. Comparison of Caspase Activation and Subcellular Localization in HL-60 and K562 Cells Undergoing Etoposide-Induced Apoptosis Blood, December 1, 1997; 90(11): 4283 - 4296. [Abstract] [Full Text] [PDF] T. Miyashita, Y. Okamura-Oho, Y. Mito, S. Nagafuchi, and M. Yamada Dentatorubral Pallidoluysian Atrophy (DRPLA) Protein Is Cleaved by Caspase-3 during Apoptosis J. Biol. Chem., November 14, 1997; 272(46): 29238 - 29242. [Abstract] [Full Text] [PDF] C. D. Jennings and K. A. Foon Recent Advances in Flow Cytometry: Application to the Diagnosis of Hematologic Malignancy Blood, October 15, 1997; 90(8): 2863 - 2892. [Full Text] [PDF] D. W. Jung, P. C. Bradshaw, and D. R. Pfeiffer Properties of a Cyclosporin-insensitive Permeability Transition Pore in Yeast Mitochondria J. Biol. Chem., August 22, 1997; 272(34): 21104 - 21112. [Abstract] [Full Text] [PDF] R. A. Brodsky, M. S. Vala, J. P. Barber, M. E. Medof, and R. J. Jones Resistance to apoptosis caused by PIG-A gene mutations in paroxysmal nocturnal hemoglobinuria PNAS, August 5, 1997; 94(16): 8756 - 8760. [Abstract] [Full Text] [PDF] L. Tentori, L. Orlando, P. M. Lacal, E. Benincasa, I. Faraoni, E. Bonmassar, S. D'Atri, and G. Graziani Inhibition of O6-Alkylguanine DNA-Alkyltransferase or Poly(ADP-ribose) Polymerase Increases Susceptibility of Leukemic Cells to Apoptosis Induced by Temozolomide Mol. Pharmacol., August 1, 1997; 52(2): 249 - 258. [Abstract] [Full Text] C. M. Eischen, T. J. Kottke, L. M. Martins, G. S. Basi, J. S. Tung, W. C. Earnshaw, P. J. Leibson, and S. H. Kaufmann Comparison of Apoptosis in Wild-Type and Fas-Resistant Cells: Chemotherapy-Induced Apoptosis Is Not Dependent on Fas/Fas Ligand Interactions Blood, August 1, 1997; 90(3): 935 - 943. [Abstract] [Full Text] [PDF] P. L. Simonian, D. A.M. Grillot, and G. Nunez Bcl-2 and Bcl-XL Can Differentially Block Chemotherapy-Induced Cell Death Blood, August 1, 1997; 90(3): 1208 - 1216. [Abstract] [Full Text] [PDF] R. D. Gascoyne, S. A. Adomat, S. Krajewski, M. Krajewska, D. E. Horsman, A. W. Tolcher, S. E. O'Reilly, P. Hoskins, A. J. Coldman, J. C. Reed, et al. Prognostic Significance of Bcl-2 Protein Expression and Bcl-2 Gene Rearrangement in Diffuse Aggressive Non-Hodgkin's Lymphoma Blood, July 1, 1997; 90(1): 244 - 251. [Abstract] [Full Text] [PDF] F. M. Uckun, Z. Yang, H. Sather, P. Steinherz, J. Nachman, B. Bostrom, L. Crotty, M. Sarquis, O. Ek, T. Zeren, et al. Cellular Expression of Antiapoptotic BCL-2 Oncoprotein in Newly Diagnosed Childhood Acute Lymphoblastic Leukemia: A Children's Cancer Group Study Blood, May 15, 1997; 89(10): 3769 - 3777. [Abstract] [Full Text] [PDF] G.-Q. Chen, X.-G. Shi, W. Tang, S.-M. Xiong, J. Zhu, X. Cai, Z.-G. Han, J.-H. Ni, G.-Y. Shi, P.-M. Jia, et al. Use of Arsenic Trioxide (As2O3 ) in the Treatment of Acute Promyelocytic Leukemia (APL): I. As2O3 Exerts Dose-Dependent Dual Effects on APL Cells Blood, May 1, 1997; 89(9): 3345 - 3353. [Abstract] [Full Text] [PDF] J.-L. Diaz, T. Oltersdorf, W. Horne, M. McConnell, G. Wilson, S. Weeks, T. Garcia, and L. C. Fritz A Common Binding Site Mediates Heterodimerization and Homodimerization of Bcl-2 Family Members J. Biol. Chem., April 25, 1997; 272(17): 11350 - 11355. [Abstract] [Full Text] [PDF] H. W. Findley, L. Gu, A. M. Yeager, and M. Zhou Expression and Regulation of Bcl-2, Bcl-xl, and Bax Correlate With p53 Status and Sensitivity to Apoptosis in Childhood Acute Lymphoblastic Leukemia Blood, April 15, 1997; 89(8): 2986 - 2993. [Abstract] [Full Text] [PDF] Y. A. Hannun Apoptosis and the Dilemma of Cancer Chemotherapy Blood, March 15, 1997; 89(6): 1845 - 1853. [Full Text] [PDF] L. M. Martins, T. Kottke, P. W. Mesner, G. S. Basi, S. Sinha, N. Frigon Jr., E. Tatar, J. S. Tung, K. Bryant, A. Takahashi, et al. Activation of Multiple Interleukin-1beta Converting Enzyme Homologues in Cytosol and Nuclei of HL-60 Cells during Etoposide-induced Apoptosis J. Biol. Chem., March 14, 1997; 272(11): 7421 - 7430. [Abstract] [Full Text] [PDF] R. S. Douglas, R. J. Capocasale, R. J. Lamb, P. C. Nowell, and J. S. Moore Chronic Lymphocytic Leukemia B Cells Are Resistant to the Apoptotic Effects of Transforming Growth Factor-beta Blood, February 1, 1997; 89(3): 941 - 947. [Abstract] [Full Text] [PDF]

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