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Glivec® (Gleevec®, Imatinib, STI571)

A Targeted Therapy for Chronic Myelogenous Leukemia
  • Elisabeth Buchdunger
  • Renaud Capdeville
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Chronic myelogenous leukemia (CML) is a clonal hematological disorder characterized by a reciprocal translocation between chromosomes 9 and 22 (1, 2) known as the Philadelphia (Ph) chromosome. The molecular consequence of this interchromosomal exchange is the creation of the bcr-abl gene coding for a protein with elevated tyrosine kinase activity. The demonstration that the expression of Bcr-Abl is both necessary and sufficient to cause a CML-like syndrome in murine bone marrow transplantation models (3, 4, 5) and the finding that the tyrosine kinase activity of Bcr-Abl is crucial for its transforming activity (6), has established the enzymatic activity of this deregulated protein as an attractive drug target addressing Bcr-Abl-positive leukemias. For the first time, a drug target was identified that very clearly differed in its activity between normal and leukemic cells. It was conceivable that this enzyme could be approached with classical tools of pharmacology since its activity, the transfer of phosphate from adenosine triphosphate (ATP) to tyrosine residues of protein substrates, could clearly be described and measured in biochemical as well as cellular assays. Furthermore, cell lines were available that were derived from human leukemic cells that had the same chromosomal abnormality. Such cell lines were instrumental for in vitro and animal studies that laid the groundwork for the clinical trials. So, the essential tools were assembled to go forward aiming at identifying potent and selective inhibitors of the Abl tyrosine kinase.

Keywords

Chronic Myeloid Leukemia Chronic Myelogenous Leukemia Imatinib Mesylate Blast Crisis Cytogenetic Response 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Elisabeth Buchdunger
    • 1
  • Renaud Capdeville
    • 2
  1. 1.Oncology ResearchNovartis Institutes for BioMedical Research Basel, Novartis Pharma AGBaselSwitzerland
  2. 2.Clinical ResearchNovartis Oncology, Novartis Pharma AGBaselSwitzerland

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