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This Article Full Text 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 Jing, Y. Articles by Waxman, S. Search for Related Content PubMed PubMed Citation Articles by Jing, Y. Articles by Waxman, S. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 January 2001, Vol. 97, No. 1, pp. 264-269 NEOPLASIA Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo Yongkui Jing, Long Wang, Lijuan Xia, Guo-qiang Chen, Zhu Chen, Wilson H. Miller, and Samuel Waxman From the Department of Medicine, Division of Medical Oncology, Mount Sinai School of Medicine, New York, NY; the Shanghai Institute of Hematology, Shanghai Second Medical University, Shanghai, China; and Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada. All-trans retinoic acid (tRA) and arsenic trioxide (As2O3) induce non-cross-resistant complete clinical remission in patients with acute promyelocytic leukemia with t(15;17) translocation and target PML-RAR, the leukemogenic protein, by different pathways suggesting a possible therapeutic synergism. To evaluate this possibility, this study examined the effect of As2O3 on tRA-induced differentiation and, conversely, the effect of tRA on As2O3-induced apoptosis. As2O3 at subapoptotic concentrations (0.5 µM) decreased tRA-induced differentiation in NB4 cells but synergized with atRA to induce differentiation in tRA-resistant NB4 subclones MR-2 and R4 cells as measured by nitroblue tetrazolium reduction and tRA-inducible genes (TTGII, RAR, RIG-E). tRA cleaved PML-RAR into distinct fragments in NB4 but not in tRA-resistant MR-2 or R4 cells, whereas As2O3 completely degraded PML-RAR in all 3 cell lines. As2O3-induced apoptosis was decreased by tRA pretreatment of NB4 cells but not of R4 cells and was associated with a strong induction of Bfl-1/A1 expression, a Bcl-2 protein family member. Severe combined immunodeficient mice bearing NB4 cells showed an additive survival effect after sequential treatment, but a toxic effect was observed after simultaneous treatment with tRA and As2O3. These data suggest that combined As2O3 and tRA treatment may be more effective than single agents in tRA-resistant patients. Although in vitro data do not always translate to in vivo response, toxicity and potential drug antagonism may be diminished by decreasing the concentration of As2O3 when given at the same time with therapeutic levels of tRA. © 2001 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: Z.-Y. Wang and Z. Chen Acute promyelocytic leukemia: from highly fatal to highly curable Blood, March 1, 2008; 111(5): 2505 - 2515. [Abstract] [Full Text] [PDF] A. Vahidnia, G.B. van der Voet, and F.A. de Wolff Arsenic neurotoxicity A review Human and Experimental Toxicology, October 1, 2007; 26(10): 823 - 832. [Abstract] [PDF] J. Lu, E.-H. Chew, and A. Holmgren Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide PNAS, July 24, 2007; 104(30): 12288 - 12293. [Abstract] [Full Text] [PDF] D. Chen, R. Chan, S. Waxman, and Y. 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	Copyright © 2001 by American Society of Hematology         Online ISSN: 1528-0020