DNA CROSS-LINKING AND REPAIR IN CISPLATIN-RESISTANT HUMAN TUMOR-CELLSFOLLOWING EXPOSURE TO A NEW CISPLATIN ANALOG, CI-973

cis-1, 1-Cyclobutanedicarboxylato(2R)-2-methyl-1 4-butanediammineplati num(II) (CI-973; NK121) is a second generation analogue of cisplatin ( CDDP). This analogue caused fewer undesirable side effects in vivo tha n CDDP and produced a tumoricidal effect superior to that of CDDP agai nst CDDP-resistant human tumor cells in vitro. However, the mechanisms responsible for the cross-sensitivity to CI-973 in these resistant ce lls have not been determined. Using a human colon carcinoma cell line (LoVo) and its CDDP-resistant counterpart (CP2.0) as study models, we found that although, on a molar basis, CI-973 was less cytotoxic than CDDP in LoVo, it partially reversed the resistance of CP2.0 cells, i.e ., the magnitude of resistance was reduced from 13-fold for CDDP to 3- fold for CI-973. We investigated DNA repair as a possible mechanism fo r the different magnitudes of resistance of these two agents. The repa ir efficiency was measured by the rate of removal of drug-induced DNA interstrand cross-links (determined with the ethidium bromide fluoresc ence binding assay) and by unscheduled DNA synthesis. Our results show ed that although the resistant CP2.0 cells were more efficient at repa iring CDDP-induced DNA cross-links than LoVo cells, the rate of repair of CI-973-induced DNA adducts in CP2.0 was significantly lower than t hat for CDDP-DNA adducts at equi-cross-linking drug concentrations. Th is difference was not observed in the sensitive LoVo cells. The concom itant association of a slower rate of removal of CI-973-induced adduct s with a lower magnitude of resistance to CI-973 suggests that a reduc ed efficiency in repairing the CI-973-induced DNA damage in CDDP-resis tant CP2.0 cells may in part contribute to the sensitivity of the resi stant cells to this novel CDDP analogue.