title: [STI571: a summary of targeted therapy].
abstract: STI571 (imatinib; Gleevec) was developed as the first molecularly targeted therapy. It was the result of an extensive search for molecules to block the aberrant activity of Abl kinase in the fusion protein Bcr-Abl. In addition, it can specifically inhibit the activity of c-Kit and PDGF receptors. This orally bioavailable drug has a low toxicity profile. It is approved to treat the patients with chronic myelogenous leukemia (CML) or gastrointestinal stromal tumor (GIST). It produces hematological, cytogenetic, and molecular remission with significant efficacy, particularly in patients with chronic-phase CML. However, there is well-documented proof of primary and secondary resistance to STI571 with progression of leukemia. More evidence indicates that this single drug may not be sufficient to completely eradicate BCR-ABL-positive stem cells. A variety of strategies has already been developed to improve the effectiveness of CML treatment, including targeting the expression or stability of the Bcr-Abl kinase itself, targeting signaling pathways activated by this kinase, as well as designing novel Abl inhibitors. In this review the molecular mechanisms of STI571 action, its effectivenes against CML, GIST, and melanoma, as well as new approaches to improve its efficacy, mainly by overcoming STI571 resistance, are discussed.
authors.affiliation: Zakład Biologii Molekularnej Nowotworów Uniwersytetu Medycznego w Łodzi. mczyz@csk.umed.lodz.pl
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Czyz
authors.forename: Justyna
authors.initials: J
authors.lastname: Jakubowska
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000187:drug effects; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D016044:Fusion Proteins, bcr-abl