Emergence of multidrug resistance in leukemia cells during chemotherapy: mechanisms and prevention.
Multifactorial resistance to extracellular stimuli is one of the major factors of tumor progression. Cells can acquire a multidrug resistant (MDR) phenotype in response to a wide variety of stress-inducing agents including chemotherapeutic drugs. In addition to the mechanisms expressed in the tumor prior to chemotherapy (presumably these mechanisms allowed tumor cells to escape the control of growth and differentiation), a complex phenotype of pleiotropic resistance is presented in the residual or recurrent tumor. This review analyzes the molecular mechanisms of MDR acquisition with the focus on hematopoietic malignancies. In particular, the chemotherapy-induced up-regulation of P-glycoprotein, a broad-specificity transmembrane efflux pump, is considered a major event in establishment of MDR in leukemia cells that were sensitive before drug exposure. The pharmacological and genetic approaches to prevent the acquisition of Pgp-mediated MDR during chemotherapy are discussed.
Shtil
Alexander A
AA
Department of Medicine and Program in Cell Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. shtilaa@yahoo.com
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005786:Gene Expression Regulation; D019450:Genes, MDR; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents