Imatinib as a paradigm of targeted therapies

Adv Cancer Res. 2004:91:1-30. doi: 10.1016/S0065-230X(04)91001-9.

Abstract

Imatinib (Gleevec) exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of the BCR-ABL tyrosine kinase as a therapeutic target in chronic myeloid leukemia and the steps in the development of an agent to specifically inactivate this abnormality. The clinical trials results are reviewed along with a description of resistance mechanisms. As imatinib also inhibits the tyrosine kinase activity of KIT and the platelet-derived growth factor receptors, the extension of imatinib to malignancies driven by these kinases will be described. Issues related to clinical trials of molecularly targeted agents are discussed, including patient and dose selection. Last, the translation of this paradigm to other malignancies is explored.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Benzamides
  • Clinical Trials as Topic
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / chemistry
  • Fusion Proteins, bcr-abl / physiology
  • Gastrointestinal Neoplasms / drug therapy
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Mice
  • Models, Molecular
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Oncogenes
  • Patient Selection
  • Piperazines / administration & dosage
  • Piperazines / pharmacology
  • Piperazines / therapeutic use*
  • Protein Conformation
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*

Substances

  • Antineoplastic Agents
  • Benzamides
  • Enzyme Inhibitors
  • Neoplasm Proteins
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl