[Multidrug resistance and its reversal. General review of fundamental aspects].
Among the mechanisms by which cancer cells evade chemotherapy, multidrug resistance (MDR) is certainly the best known. MDR is characterised by cross-resistance between numerous natural products used in cancer treatment, especially antibiotics and plant alkaloids. MDR results from a defect in cell accumulation of the drugs, which are actively effluxed from cells by a plasma membrane pump, which is a high molecular weight glycoprotein termed P-glycoprotein. This protein is encoded by a gene called mdr1, and can be inhibited by a variety of pharmacological compounds. The activation of the mdr1 gene can occur via numerous types of stimulation, especially anticancer drugs themselves, which can induce mdr1 gene transcription. P-glycoprotein is an ATPase transporter which is believed to extrude xenobiotics from the plasma membrane rather than from cytoplasm. Although potential sites of interaction of P-glycoprotein with its various ligands have been identified, especially at the level of putative transmembrane domains, the exact mechanism for drug pumping has never been elucidated. Reversal of MDR in vitro is easy to obtain and to characterise. An important development aims at identifying substances able to reverse MDR in the clinical setting, that are devoid of any pharmacological properties other than interaction with P-glycoprotein. Other targets can be postulated for these MDR modulators, whose combination could well lead to a synergistic reversal of drug resistance.
Robert
J
J
Institut Bergonié, université de Bordeaux, France.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D000970:Antineoplastic Agents / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005786:Gene Expression Regulation; D006801:Humans
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents
La multidrug resistance et sa réversion. Revue générale des aspects fondamentaux.