We have reported the establishment of a
mitomycin-C (MMC)-resistant
non-small-cell lung-cancer cell line, PC-9/MC4. As determined by an MTT assay, this resistant cell line was found to be 4 times more sensitive to
adriamycin (ADM) than was the parental PC-9. There were no significant differences in sensitivity to
etoposide,
mitoxantrone,
daunomycin,
epirubicin,
pirarubicin, 9-aminoanthracycline or 3'-deamino-3'-morpholino-13-deoxo-10-hydroxy
carminomycin. These data suggest that neither qualitative or quantitative changes in
DNA topoisomerase II nor the enhanced repair of
DNA can explain the differing sensitivity to ADM observed. No significant differences were found in the accumulation of ADM and
glutathione (GSH) in these cell lines. Although total
glutathione-S-transferase (GST) activity in PC-9/MC4 cells was lower than that observed in PC-9 cells and treatment with
ethacrynic acid (EA) reduced sensitivity to ADM in both cell lines, relative resistance was unaffected.
NADH-cytochrome b5 reductase (B5R) activity in PC-9/MC4 cells showed a 3-fold greater decrease than that in PC-9 cells, and
DT-diaphorase (DTD) activity in PC-9/MC4 cells showed an approximately 200-fold greater decrease than that in PC-9 cells. Addition of
dicumarol, an inhibitor of DTD, decreased the sensitivity of ADM of PC-9 but not of PC-9/MC4. DTD activity in the PC-9 cell line was inhibited by treatment with
dicumarol while in PC-9/MC4 it remained unchanged. These data suggest that
DT-diaphorase is a determinant of sensitivity to ADM in the 2 cell lines.