Resistance of paraquat and adriamycin in human breast tumor cells: role of free radical formation.
Generation and enhanced detoxification of toxic free radicals by glutathione peroxidase and glutathione transferase in human breast tumor cells have been suggested to play an important role in toxicity and in resistance to adriamycin. We have examined the biochemical basis of paraquat-induced free radical formation and the mechanism of resistance to this agent in human breast tumor cell lines. We have also compared the similarities and differences between adriamycin and paraquat in their mode of free radical formation and tumor cell kill. Anaerobic incubation of paraquat resulted in the formation of the paraquat cation radical in both the sensitive and resistant cells which increased with time and was enhanced by NADPH addition. Our studies show that while both adriamycin and paraquat form hydroxyl radicals (.OH) in these cell lines, adriamycin was 2-3 fold better at reducing oxygen. The formation of .OH was inhibited by exogenously added superoxide dismutase and catalase, indicating the involvement of both superoxide anion radical and hydrogen peroxide. In the adriamycin-resistant cell line, less .OH was formed by each of these drugs. While the .OH appeared to be formed outside by both adriamycin and paraquat in the drug-sensitive cells, experiments using chromium oxalate as a spin-broadening agent suggest that the drug-induced .OH formation in the resistant cells is an intracellular event. The adriamycin-resistant cell line was also cross-resistant to paraquat, suggesting a common mechanism of toxicity for both drugs. However, adriamycin was significantly more toxic (4000-times) to the sensitive cells suggesting that either other mechanisms or site-specific free radical formation are also important in biochemical mechanisms of adriamycin toxicity.
Sinha
B K
BK
Biochemical Pharmacology Branch, National Cancer Institute, Bethesda, MD 20892.
Dusre
L
L
Collins
C
C
Myers
C E
CE
D001943:Breast Neoplasms / Q000473:pathology; D002857:Chromium / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D003630:Daunorubicin / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D006878:Hydroxides; D017665:Hydroxyl Radical; D010269:Paraquat / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D006878:Hydroxides; D002857:Chromium; D017665:Hydroxyl Radical; D004317:Doxorubicin; D004247:DNA; D010269:Paraquat; D003630:Daunorubicin