Basic science going clinical: molecularly targeted therapy of chronic myelogenous leukemia.
Imatinib (STI571), a 2-phenylaminopyrimidine, specifically inhibits the tyrosine kinase activity of Abl, Kit, and platelet-derived growth factor receptor. Clinical trials in chronic myelogenous leukemia (CML), characterized by the constitutively active Bcr-Abl tyrosine kinase, and gastrointestinal stromal tumors, characterized by activating mutations of Kit, have shown excellent results. This success is proof of principle for the concept of molecularly targeted therapy: rational treatment based on the recognition of the causal lesion responsible for malignant growth. In this manuscript, the preclinical and clinical development of imatinib for the treatment of CML will be reviewed. Room will be given to problems and challenges that may be typical of molecularly targeted therapy in general, such as the emergence of resistance as a result of point mutations. Last, the question will be addressed, why imatinib is so successful, and whether its success might be reproducible in other malignant conditions.
Deininger
Michael W N
MW
BMT/Leukemia Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road L592, Portland 97239, USA. deininge@ohsu.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C099852:PDGF receptor tyrosine kinase; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor; D016315:Proto-Oncogene Proteins c-abl