Resistance to inhibitors of DNA topoisomerases.
Studies examining the mechanisms of resistance to camptothecin and its water-soluble analogs have been reported only recently. None of these studies have involved resistance derived in vivo in humans. Some of the mechanisms already describe could be predicted from the mechanism of action of the drug and from prior studies in yeast. It is interesting that, to date, the only mechanisms of resistance relate directly to the target of the drug, DNA topoisomerase I, and that the drugs are active in cell lines exhibiting the multidrug-resistant phenotype. Should camptothecin analogs prove as active in human clinical trials as animal tests predict, it will be interesting to see if additional mechanisms of resistance emerge from studies in treated patients. On the other hand, if clinical activity is similar to that demonstrated by camptothecin 15 years ago, the issue will be of academic interest only.
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Sullivan
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Ross
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001692:Biological Transport; D002166:Camptothecin / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002453:Cell Cycle; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004270:DNA, Circular / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D007941:Leukemia P388 / Q000201:enzymology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D011485:Protein Binding; D013347:Subcellular Fractions / Q000201:enzymology; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004270:DNA, Circular; D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; D007364:Intercalating Agents; D008562:Membrane Glycoproteins; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000255:Adenosine Triphosphate; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin