Mechanisms of resistance to imatinib (STI571) and prospects for combination with conventional chemotherapeutic agents.
Imatinib (STI571, Glivec) is a small molecule drug selected for its ability to inhibit the Bcr-Abl kinase, the pathogenic molecular abnormality in chronic myelogenous leukemia (CML). It also is an efficient inhibitor of the Kit and platelet-derived growth factor receptor tyrosine kinases. In vitro studies have demonstrated that this drug potently inhibits proliferation and induces apoptosis of cells that depend on activation of these kinases. Phase I clinical studies have demonstrated remarkable activity against CML. However, these studies, as well as a variety of experimental models, have suggested that clinical resistance to STI571 could develop. The mechanisms for the development of this resistance will be discussed along with the potential for circumventing STI571 resistance by combining it with traditional anti-neoplastic agents.
Krystal
G W
GW
Department of Medicine, Medical College of Virginia, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA. gkrystal@hsc.vcu.edu
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005784:Gene Amplification / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D009369:Neoplasms / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases