Perspectives on the development of a molecularly targeted agent.
STI571 (Gleevec, imatinib mesylate) exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of Bcr-Abl as a therapeutic target in chronic myelogenous leukemia and the steps in the development of an agent to specifically inactivate this abnormality. Issues related to clinical trials of molecularly targeted agents are discussed, including dose and patient selection, as are possible mechanisms of resistance to STI571. Lastly, the potential use of STI571 in other malignancies and the translation of this paradigm to other malignancies is explored.
Druker
Brian J
BJ
Leukemia Center, Oregon Health & Science University Cancer Institute, 3181 SW Sam Jackson Park Road, Portland 97201, USA. drukerb@ohsu.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D001665:Binding Sites; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology; D010879:Piperazines / Q000627:therapeutic use*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl