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Imatinib Mesylate (Gleevec®) and the Emergence of Chemotherapeuticss Drug-Resistant Mutations

  • Gerald V. Denis
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Summary

Imatinib mesylate (Gleevec® Novartis) is an important, new, molecularly targeted, anti-cancer agent with clinical efficacy in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST). These malignancies develop after constitutive activation of Abelson (Abl) or c-kit (CD117) tyrosine kinases, respectively; Imatinib specifically inhibits such kinase activity. Many CML and GIST patients have relapsed while on imatinib treatment, however. The emergence of resistance to imatinib chemotherapeutic intervention is in retrospect neither surprising nor insoluble. Principles previously used to develop combination chemotherapy to avoid the development of multidrug resistance in leukemias and lymphomas (and later used in developing combinations for treatment of human immunodeficiency virus infections) may prove useful in the approach to the next generation of targeted molecular therapeutics for CML. In general, multidrug protocols and agents targeted to mutation sites simultaneously are likely to have a greater chance of success than single-agent therapy.

Key Words

Imatinib mesylate Gleevec STI-571 drug resistance cancer chemotherapy chronic myelogenous leukemia gastrointestinal stromal tumor BCR-ABL c-kit stem cell factor structural biology 

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© Humana Press 2008

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  • Gerald V. Denis

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