Deficient activation by a human cell strain leads to mitomycin resistance under aerobic but not hypoxic conditions.
Two non-transformed human skin fibroblast strains, GM38 and 3437T, were found to be more sensitive to the bioreductive alkylating agents mitomycin C (MMC) and porfiromycin (PM) under hypoxic compared to aerobic conditions. One of these strains, 3437T, was 6-7 times more resistant to these agents under aerobic exposure conditions, but was identical in sensitivity to the normal strain, GM38, under hypoxic conditions. Aerobic 3437T cells demonstrated no increased resistance to cisplatin compared to the normal strain, arguing against enhanced ability to repair DNA interstrand cross-links as the underlying explanation for the mitomycin resistance. The aerobic resistance of 3437T was not altered by dicumarol, an inhibitor of the enzyme DT-diaphorase which is believed to be involved in aerobic activation of MMC and PM. Dicumarol did increase the resistance of GM38, but not to the same level of resistance demonstrated by 3437T. These results suggest that the aerobic MMC and PM resistance of 3437T may arise, in part, from a deficiency in DT-diaphorase activity. The identical sensitivities under hypoxic conditions indicate that drug activation pathways operative in the absence of oxygen are similar in both the normal and 3437T cells.
Marshall
R S
RS
Physics Division, Ontario Cancer Institute, Toronto, Canada.
Paterson
M C
MC
Rauth
A M
AM
D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D001728:Dicumarol / Q000494:pharmacology; D004351:Drug Resistance; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016685:Mitomycin; D008937:Mitomycins / Q000493:pharmacokinetics* / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D011160:Porfiromycin / Q000493:pharmacokinetics / Q000494:pharmacology; D012867:Skin / Q000166:cytology*
D008937:Mitomycins; D016685:Mitomycin; D001728:Dicumarol; D011160:Porfiromycin; D010100:Oxygen