Mechanisms of resistance to STI571 (Imatinib) in Philadelphia-chromosome positive acute lymphoblastic leukemia.
Resistance against STI571 (Imatinib) appears to be multifactorial, but the most likely mechanisms can be broadly categorized as interference with the pharmacologic activity of STI571 or genetic changes which alter the biologic behaviour of the leukemic cells. In Ph + ALL, responses to STI571 are not sustained, and in the overwhelming majority of patients development of resistance is rapid. Clinically, two types of resistance to STI571 can be distinguished: 'primary resistance', corresponding to a failure to achieve fewer than 5% blasts in the bone marrow, and 'secondary resistance' in patients with STI571-induced complete remission who relapse despite continued STI571 treatment. Attempts to identify mechanisms by which Ph + ALL acquire resistance to STI571 have already been successful. Mutations in the ATP binding site of ABL are frequent events which counteract the antileukemic effect of STI571. Gene expression profiling has been shown to discriminate between resistant and sensitive leukemic cells. Application of this technique has also generated several hypotheses regarding the ability of leukemic cells to bypass the BCR-ABL signal transduction pathway. This may result in the proliferation of Ph + leukemic cells even in the presence of STI571.
Hofmann
Wolf-K
WK
Department of Hematology and Oncology, University Hospital, Frankfurt/Main, Germany. w.k.Hofmann@em.uni-frankfurt.de
Komor
Martina
M
Hoelzer
Dieter
D
Ottmann
Oliver G
OG
D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000235:genetics* / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D000068877:Imatinib Mesylate; D009154:Mutation; D016374:Oncogene Proteins v-abl / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use
D001549:Benzamides; D016374:Oncogene Proteins v-abl; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate