Keynote address: multidrug resistance: a pleiotropic response to cytotoxic drugs.
Tumor cells exposed in tissue culture to one of several different classes of antineoplastic agents, including anthracyclines, vinca alkaloids, epipodophyllotoxins, and certain antitumor antibiotics, can develop resistance to the selecting agent and cross resistance to the other classes of agents. This phenomena of multidrug resistance is generally associated with decreased drug accumulation and overexpression of a membrane glycoprotein. This membrane protein, referred to as P-glycoprotein, apparently acts as an energy-dependent drug efflux pump. Multidrug resistance in human MCF-7 breast cancer cells selected for resistance to adriamycin (AdrR MCF-7) is associated with amplification and overexpression of the mdr1 gene which encodes P-glycoprotein. A number of other changes are also seen in this resistant cell line including alterations in Phase I and Phase II drug metabolizing enzymes. Similar biochemical changes occur in a rat model for hepatocellular carcinogenesis and are associated in that system with broad spectrum resistance to hepatotoxins. The similar changes in these two models of resistance suggests that these changes might be part of a battery of genes whose expression can be altered in response to cytotoxic stress, thus rendering the cell resistant to a wide variety of cytotoxic agents.
Fairchild
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CR
Medicine Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20892.
Cowan
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KH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004351:Drug Resistance; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000502:physiology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D005982:Glutathione Transferase