CYTOTOXICITY OF A NOVEL INDOLOQUINONE EO9 IN HYPOXIC NON-SMALL-CELL LUNG-CANCER CELL-LINES

methyl-[1H-indole-4,7-dione]-prop-beta-en-alpha-ol (EO9) is a bioreduc tive anticancer agent active for non-small cell lung cancer (NSCLC) an d structurally related to mitomycin C (MMC). DT-diaphorase (DTD) is re garded as a two electron reductase that plays an important role in the biotransformation of MMC to antitumor metabolites. To evaluate the ro le of DTD as a bioactivator of EO9 in NSCLC cell lines under oxic and hypoxic conditions, we examined the inhibitory effect of dicumarol whi ch was regarded as a selective inhibitor of DTD on the sensitivity to EO9 in vitro. In this study, we used an MMC-resistant NSCLC cell line (PC-9/MC4) which was established from a PC-9 cell line as a parent cel l line by continuous exposure to MMC in our laboratory. We reported pr eviously that the subline PC-9/MC4 was 6.7-fold more resistant to MMC than PC-9 with decreased DTD activity. The IC50 value of PC-9 against EO9 was significantly increased by co-incubation with dicumarol under oxic conditions. EO9 was more cytotoxic against PC-9/MC4 than against PC-9 cells and the enhancement was impaired by tempol under hypoxic co nditions. These findings suggest a suppressive role of DTD against one -electron reduction pathway in the bioactivation of EO9 under hypoxic conditions and EO9 may be more active against oxygen-deficient solid t umors especially in MMC-resistant NSCLC cells with low levels of DTD a ctivity.