Efficacy of dual-specific Bcr-Abl and Src-family kinase inhibitors in cells sensitive and resistant to imatinib mesylate Journal Article
| Authors: | Tipping, A. J.; Baluch, S.; Barnes, D. J.; Veach, D. R.; Clarkson, B.; Bornmann, W. G.; Mahon, F. X.; Goldman, J. M.; Melo, J. V. |
| Article Title: | Efficacy of dual-specific Bcr-Abl and Src-family kinase inhibitors in cells sensitive and resistant to imatinib mesylate |
| Abstract: | Monotherapy of chronic myeloid leukemia (CML) with imatinib mesylate has been cast into shadow by the evolution of clinical resistance during therapy. Resistance to imatinib can arise by multiple mechanisms including amplification or mutation of Bcr-Abl, and continuity of imatinib therapy is probably a poor option for either of these patient groups. Recently, however, a structurally distinct new class of drugs, the pyrido[2,3-d]pyrimidines, has been described, and these compounds are predicted to make different molecular contacts in the Abl kinase domain. These drugs potently target both the Bcr-Abl and Src-family kinase activities, both of which are thought to be relevant to survival of the leukemic cell. We asked whether these drugs could selectively induce cell death in murine cell line models of CML cells sensitive and resistant to imatinib by different mechanisms. We show that whereas the pyrido[2,3-d] pyrimidines are indeed highly potent in suppressing proliferation of Bcr-Abl-overexpressing imatinib-resistant cells, they are almost completely ineffective against cells expressing the T315I mutant. This implies that despite structural differences from imatinib, these drugs are unlikely to be useful in patients expressing this mutant Bcr-Abl protein, but may be effective in cases where selection of cells overexpressing the oncoprotein leads to refractoriness to imatinib. © 2004 Nature Publishing Group All rights reserved. |
| Keywords: | controlled study; treatment outcome; unclassified drug; drug efficacy; nonhuman; cell proliferation; animal cell; mouse; animals; mice; cell death; cell survival; cell division; imatinib; gene overexpression; apoptosis; enzyme inhibition; drug potency; drug resistance; dose-response relationship, drug; drug resistance, neoplasm; cell line, tumor; 6 (2,6 dichlorophenyl) 2 [3 (hydroxymethyl)anilino] 8 methylpyrido[2,3 d]pyrimidin 7(8h) one; protein tyrosine kinase; chronic myeloid leukemia; pyrimidines; protein tyrosine kinase inhibitor; drug delivery systems; drug mechanism; cell culture; enzyme inhibitors; leukemia cell; western blotting; protein-tyrosine kinases; bcr abl protein; piperazines; src-family kinases; concentration (parameters); fusion proteins, bcr-abl; concentration response; polyacrylamide gel electrophoresis; imatinib mesylate; leukemia, myeloid, chronic; humans; priority journal; article; pyrido[2,3-d] pyrimidines; ski dv mo17; ski dv1 10; ski dv2 47 |
| Journal Title: | Leukemia |
| Volume: | 18 |
| Issue: | 8 |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2004-06-17 |
| Start Page: | 1352 |
| End Page: | 1356 |
| Language: | English |
| DOI: | 10.1038/sj.leu.2403416 |
| PROVIDER: | scopus |
| PUBMED: | 15201856 |
| DOI/URL: | |
| Notes: | Leukemia -- Cited By (since 1996):27 -- Export Date: 16 June 2014 -- CODEN: LEUKE -- Source: Scopus |
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