CHARACTERIZATION OF CAMPTOTHECIN-RESISTANT CHINESE-HAMSTER LUNG-CELLS

Three camptothecin-resistant sublines (V79r, IRS-1r and IRS-2r) of V79 cells and their irradiation-sensitive mutants, IRS-1 and IRS-2, were developed by stepwise, continuous exposure to camptothecin (CPT). The degree of resistance varied among these cells. Based on the biochemical characterizations of these resistant cell lines, the mechanisms which could be responsible for the resistance of CPT were proposed to be: (a) a decrease in the intracellular accumulation of CPT with or without alteration of DNA topoisomerase I, (b) a decrease in the amount of DNA topoisomerase I, or (c) a decrease in the sensitivity of DNA topoisomerase I to CPT. The resistant cells which exhibited down-regulation of DNA topoisomerase I were collaterally sensitive to etoposide (VP-16) and its analogue, 4'-demethy-4-beta-(4"-fluoroanilino)-4-desoxypodophyll?? otoxin, despite the fact that there were equal amounts of DNA topoisomerase II in the parental and in the resistant cell lines. Alternating the usage of CPT and VP-16 for the treatment of cancer is indicated.