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Blood, 1 February 2006, Vol. 107, No. 3, pp. 898-903. Prepublished online as a Blood First Edition Paper on October 18, 2005; DOI 10.1182/blood-2005-06-2430. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-06-2430v1 107/3/898    most recent 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 Batova, A. Articles by Yu, A. L. Search for Related Content PubMed PubMed Citation Articles by Batova, A. Articles by Yu, A. L. Related Collections Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS EFA (9--D-erythrofuranosyladenine) is an effective salvage agent for methylthioadenosine phosphorylase-selective therapy of T-cell acute lymphoblastic leukemia with L-alanosine Ayse Batova, Howard Cottam, John Yu, Mitchell B. Diccianni, Carlos J. Carrera, and Alice L. Yu From the Departments of Pediatrics/Hematology-Oncology and Medicine, University of California San Diego, San Diego, CA; and the Institute of Cellular and Organismic Biology and The Genomics Research Center, Academia Sinica, Taipei, Taiwan. The deficiency of methylthioadenosine phosphorylase (MTAP) in T-cell acute lymphoblastic leukemia (T-ALL) and other cancers, while constitutively expressed in normal cells, allows for selective therapy using L-alanosine, an inhibitor of de novo AMP synthesis. We demonstrate that MTAP- T-ALL cells obtained at relapse are as sensitive to L-alanosine toxicity as diagnosis samples. The therapeutic index of L-alanosine can be increased by the use of a MTAP substrate, which protects MTAP+ normal cells. Since MTAP substrates MTA and 5'deoxyadenosine are prone to toxicities associated with adenosine, we synthesized and evaluated a potentially nontoxic MTAP substrate, 9--D-erythrofuranosyladenine (EFA). The cytotoxicity of EFA to hematopoietic progenitors erythroid burst-forming units (BFU-Es) and granulocyte-macrophage colony-forming units (CFU-GMs) was at least 26- to 41-fold less than that of MTA. In addition, EFA selectively rescued MTAP+ MOLT-4 cells from L-alanosine toxicity at 25 µM with negligible toxicity even at 100 µM. As for MTA, significant, albeit incomplete, rescue was achieved at 12.5 µM, but higher concentrations were toxic. EFA at 20 µM or less rescued primary MTAP+ T-ALL cells and normal lymphocytes from L-alanosine toxicity. Collectively, these data indicate that EFA is an effective agent for salvaging MTAP+ cells from L-alanosine toxicity and is superior to MTA due to lower cytotoxicity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Marce, O. Balague, L. Colomo, A. Martinez, S. Holler, N. Villamor, F. Bosch, G. Ott, A. Rosenwald, L. Leoni, et al. Lack of methylthioadenosine phosphorylase expression in mantle cell lymphoma is associated with shorter survival: implications for a potential targeted therapy. Clin. Cancer Res., June 15, 2006; 12(12): 3754 - 3761. [Abstract] [Full Text] [PDF]

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