[How do cancers resist to chemotherapy?].
Resistance is often defined as a lack of therapeutic response. Cellular resistance involves a decrease in intracellular levels of the antitumor agent due to a variety of mechanisms. These mechanisms are active in tumors with initial resistance as well as in those which respond initially but fail to be completely destroyed by chemotherapy. Although acquired forms of resistance seem to be the result of selection, some studies suggest that antitumor agents may induce resistance. Four main mechanisms of resistance are currently being investigated: 1) multidrug resistance, involving expression of a membrane P-glycoprotein, responsible for resistance to hydrophobic cationic agents; 2) detoxification of hydrophilic agents by the enzyme glutathione-S-transferase; 3) increased production of enzymes targeted by antimetabolites; 4) mutation or decreased synthesis of topoisomerases I and II which are the targets of very recent antitumor agents. New data were presented at the 1992 symposium of the American Association for Cancer Research; expression of P-glycoprotein is controlled by the mutant protein P53, the oncogene ras and differentiation agents. Physiological effects of this molecule are related to the chloride pump. Bone marrow stem cells from transgenic mice obtained by transfection of the gene MDR1 in germ cells exhibit resistance. Many agents can reverse P-glycoprotein-related resistance. Results from three phase I trials with Cyclosporin A as reversion agent were reported. It is essential to conduct clinical trials in order to assess the true value of these new data which hold promise for improving the performance of antitumor agents.
Institut Curie Biologie, Paris, France.
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Poupon
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D004351:Drug Resistance / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D008562:Membrane Glycoproteins
Comment les cancers échappent-ils à la chimiothérapie?