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New targeted therapies for chronic myelogenous leukemia: opportunities to overcome imatinib resistance.

Abstract
The advent of tyrosine kinase inhibitors (TKIs) has ushered in a new era in the management of chronic myelogenous leukemia (CML). Imatinib, the first TKI to be approved for the treatment of CML and the current standard first-line therapy, has significantly improved the prognosis of patients with CML. Nevertheless, a minority of patients in chronic-phase CML and even more patients with advanced-phase disease demonstrate resistance to imatinib or develop resistance during treatment. In 40% to 50% of cases, this is attributed to the development of mutations that impair the ability of imatinib to bind to and inhibit the constitutively active Bcr-Abl kinase. Consequently, researchers have developed novel, more potent TKIs that can overcome not only Bcr-Abl-dependent mechanisms of resistance, but also those that are Bcr-Abl-independent. These include: dasatinib, a potent dual Bcr-Abl and Src inhibitor; nilotinib, a selective, potent Bcr-Abl inhibitor; bosutinib (SKI-606) and INNO-406 (NS-187), which are both Src-Abl inhibitors; and others. Combination therapy is also being explored concurrently using agents that affect a variety of oncogenic pathways and immune modulation. Herein, we review some of these strategies, particularly those for which clinical data are currently available.
AuthorsElias Jabbour, Jorge Cortes, Susan O'Brien, Francis Giles, Hagop Kantarjian
JournalSeminars in hematology (Semin Hematol) Vol. 44 Issue 1 Suppl 1 Pg. S25-31 (Jan 2007) ISSN: 0037-1963 [Print] United States
PMID17292738 (Publication Type: Journal Article, Review)
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Aniline Compounds
  • Benzamides
  • Cancer Vaccines
  • Nitriles
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Quinolines
  • TOM1L1 protein, human
  • Thiazoles
  • bosutinib
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • nilotinib
  • bafetinib
  • Dasatinib
Topics
  • Adaptor Proteins, Signal Transducing (antagonists & inhibitors)
  • Aniline Compounds (pharmacology)
  • Benzamides
  • Cancer Vaccines
  • Clinical Trials as Topic
  • Dasatinib
  • Drug Resistance, Neoplasm (drug effects, physiology)
  • Fusion Proteins, bcr-abl (drug effects, genetics)
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, physiopathology)
  • Nitriles (pharmacology)
  • Piperazines (pharmacology)
  • Protein Kinase Inhibitors (pharmacology)
  • Protein-Tyrosine Kinases (antagonists & inhibitors)
  • Pyrimidines (pharmacology)
  • Quinolines (pharmacology)
  • Thiazoles (pharmacology)

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