Mechanisms of antifolate resistance and methotrexate efficacy in leukemia cells.
Antifolates are the first class of antimetabolites introduced to clinic about 6 decades ago. Now, after several years of administration of antifolates against malignancies and particularly leukemia, we are still trying to achieve a full understanding of the mechanisms of action and resistance to these agents. The present article covers different factors able to influence efficacy of antifolates on leukemic cells, the known mechanisms of resistance to methotrexate (MTX) and strategies to overcome these mechanisms. The dominant factors that are contributed to tolerance to cytocidal effects of MTX including pharmacokinetic factors, impaired transmembrane uptake as the most frequent rote of provoking resistance to MTX, augmented drug efflux, impaired intracellular polyglutamation as a determining process of drug efficacy, alterations in expression or activity of target enzymes and increased intracellular folate pools; and finally role of 7-hydroxymethotrexate on response or resistance to MTX will be discussed in more detail. Finally, strategies to overcome resistance to antifolates are discussed.
Fotoohi
Alan Kambiz
AK
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Albertioni
Freidoun
F
D000970:Antineoplastic Agents; D001692:Biological Transport; D019008:Drug Resistance, Neoplasm; D005493:Folic Acid Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D053858:Metabolic Networks and Pathways; D008727:Methotrexate / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D008727:Methotrexate