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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3270-3277. Prepublished online as a Blood First Edition Paper on December 16, 2004; DOI 10.1182/blood-2004-10-3864. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-10-3864v1 105/8/3270    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 Gu, J. J. Articles by Mitchell, B. S. Search for Related Content PubMed PubMed Citation Articles by Gu, J. J. Articles by Mitchell, B. S. Related Collections Neoplasia Apoptosis Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Synergy between imatinib and mycophenolic acid in inducing apoptosis in cell lines expressing Bcr-Abl Jing Jin Gu, Lalaine Santiago, and Beverly S. Mitchell From the Lineberger Comprehensive Cancer Center, Departments of Pharmacology and Medicine, University of North Carolina at Chapel Hill. Bcr-Abl tyrosine kinase activity initiates a number of intracellular signaling cascades that result in leukemogenesis. Imatinib mesylate, a specific Bcr-Abl tyrosine kinase inhibitor, has been highly successful in the treatment of chronic myelogenous leukemia (CML). However, the emergence of imatinib resistance and the incomplete molecular response of a significant number of patients receiving this therapy have led to a search for combinations of drugs that will enhance the efficacy of imatinib. We have demonstrated that mycophenolic acid (MPA), a specific inosine monophosphate dehydrogenase (IMPDH) inhibitor that results in depletion of intracellular guanine nucleotides, is synergistic with imatinib in inducing apoptosis in Bcr-Abl-expressing cell lines. Studies of signaling pathways downstream of Bcr-Abl demonstrated that the addition of MPA to imatinib reduced the phosphorylation of both Stat5 and Lyn, a Src kinase family member. The phosphorylation of S6 ribosomal protein was also greatly reduced. These results demonstrate that inhibitors of guanine nucleotide biosynthesis may synergize with imatinib in reducing the levels of minimal residual disease in CML and lay the foundation for clinical trials in which IMPDH inhibitors are added to imatinib in patients who have suboptimal molecular responses to single agent therapy or who have progressive disease. (Blood. 2005; 105:3270-3277) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Baccarani, G. Saglio, J. Goldman, A. Hochhaus, B. Simonsson, F. Appelbaum, J. Apperley, F. Cervantes, J. Cortes, M. Deininger, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet Blood, September 15, 2006; 108(6): 1809 - 1820. [Abstract] [Full Text] [PDF] T.-C. Chou Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies Pharmacol. Rev., September 1, 2006; 58(3): 621 - 681. [Abstract] [Full Text] [PDF] V. G. Karur, C. A. Lowell, P. Besmer, V. Agosti, and D. M. Wojchowski Lyn kinase promotes erythroblast expansion and late-stage development Blood, September 1, 2006; 108(5): 1524 - 1532. [Abstract] [Full Text] [PDF]

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