Tumour cell resistance to anthracyclines--a review.
Resistance to anthracyclines is the major factor limiting their clinical utility. Laboratory studies using cultured experimental and human tumour cells have indicated that reduced intracellular drug accumulation is one important factor underlying resistance. In some systems this results from enhanced active drug efflux, a process which may be circumvented experimentally, for example by calcium antagonists. A specific glycoprotein which is produced in excess and is inherited has been identified in the cell membrane of certain anthracycline-resistant cells, while gene amplification with the appearance of double-minute chromosomes has been noted in others. Thus it is possible that anthracycline resistance arises following inherited changes in the cell membrane resulting in failure of drug accumulation. However, other possibilities exist, including differences in drug binding, either to the cell membrane or to nuclei, differences in metabolism to the semiquinone free radical, and differences in drug penetration related to tumour morphology. For each human tumour type the factor(s) involved may differ, but sufficient clues now exist to suggest that clinical testing of some of the therapeutic possibilities for circumventing anthracycline resistance may soon be appropriate.
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Merry
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D000818:Animals; D000903:Antibiotics, Antineoplastic; D001693:Biological Transport, Active / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004317:Doxorubicin / Q000627:therapeutic use; D004351:Drug Resistance; D004357:Drug Synergism; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D005784:Gene Amplification; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D008560:Membrane Fluidity; D008970:Molecular Weight; D009279:Naphthacenes / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D002121:Calcium Channel Blockers; D002147:Calmodulin; D005609:Free Radicals; D006023:Glycoproteins; D009279:Naphthacenes; D004317:Doxorubicin; D004247:DNA; D013762:Tetrahydrofolate Dehydrogenase