ESTABLISHMENT AND CHARACTERIZATION OF NONSMALL CELL LUNG-CANCER CELL-LINES RESISTANT TO MITOMYCIN-C UNDER AEROBIC CONDITIONS

To elucidate the mechanisms of acquired resistance to mitomycin C (MMC ) in non-small cell lung cancer (NSCLC), we established two MMC-resist ant NSCLC sublines by continuous exposure to MMC, using PC-9 as a pare nt cell line. The sublines, PC-9/MC2 and PC-9/MC4, were 6.4- and 10-fo ld more resistant to MMC than their parent cell line, respectively, at the IC50 value as determined by MTT assay. They exhibited cross-resis tance to EO9, but were not resistant to cisplatin, vindesine, etoposid e, carboquone, or KW-2149, a novel MMC derivative. They were collatera lly sensitive to adriamycin and menadione. Accumulation of the drug wa s decreased in the resistant sublines to about 60% of that in the pare nt cells. Cytosolic DT-diaphorase (DTD) activities were decreased to 1 3.5+/-3.2 in PC9/MC2 and 1.3+/-0.6 in PC-9/MC4 from 261.5+/-92.7 nmol/ min/mg protein in the parent PC-9. NADH:cytochrome b(5) reductase acti vities in both of the resistant cell lines were significantly decrease d as compared to that in the parent cell line. Addition of dicumarol r esulted in a two-fold increase in IC50 value in PC-9, whereas the IC50 value showed no change in PC-9/MC4. Moreover, dicumarol did not affec t the sensitivities to KW-2149 but decreased the sensitivities to EO9 in both the parent and the resistant cell lines. Formation of an alkyl ating metabolite was significantly decreased in the resistant cells, i n parallel to the degree of resistance. We concluded that deficient dr ug activation due to decreased DTD activity was important as a mechani sm of resistance to MMC in PC-9, a relatively DTD rich NSCLC cell line .