MODULATION OF SENSITIVITY TO MITOMYCIN-C AND A DITHIOL ANALOG BY TEMPOL IN NON-SMALL-CELL LUNG-CANCER CELL-LINES UNDER HYPOXIA

We examined the mechanisms involved in the bioactivation of mitomycin C (MMC) and a newly developed MMC analogue: gamma-L-glutamylamino)ethy l]dithio}ethyl)mitomycin C, KW-2149, in non-small-cell lung cancer (NS CLC) cell lines under aerobic and hypoxic conditions. To investigate t hese mechanisms, we used MMC-resistant non-small-cell lung cancer cell lines (PC-9/MC4) that had been established in our laboratory from the parent PC-9 cell line by continuous exposure to MMC. We previously re ported that the MMC-resistant cell line (PC-9/MC4) was poor in NAD(P)H dehydrogenase (quinone) activity and approximately 6-fold more resist ant than the parent cells (PC-9) to MMC on 2-h exposure under aerobic conditions. In this study, the subline PC9/MC4 was 6.7-fold more resis tant to MMC than PC-9, the parent cell line, under aerobic conditions, and 5.2-fold more resistant under hypoxic conditions after 2h exposur e to MMC. However, on co-incubation with tempol, an inhibitor of the o ne-electron reduction pathway, the sensitivity of PC-9/MC4 to MMC was impaired under hypoxic conditions, but the impairment was not evident under aerobic conditions. KW-2149, the newly developed MMC analogue, w as cytotoxic for both PC-9/MC4 and PC-9 cells, and the sensitivity of both cell lines to KW-2149 was not changed by exposure to hypoxic cond itions or by coincubation with tempol. There were no significant diffe rences in the intracellular uptake of MMC and the activities of cytoso lic detoxification enzymes between the PC-9 and PC-9/MC4 cell lines. T hese results support the hypothesis that the one-electron reduction pa thway plays a partial role in the bioactivation of MMC, but not of KW- 2149, and that KW-2149 is excellent at circumventing resistance to MMC in NSCLC.