Characterization of acquired resistance to cis-diamminedichloroplatinum (II) in BE human colon carcinoma cells

To study mechanisms underlying resistance to cis-diamminedichloroplatinum (II) (cis-DDP) we have induced resistance to this agent in BE human colon carcinoma cells. A 5-fold increase in the IC50 of resistant compared to sensitive cells was noted as analyzed by the inhibition of cellular growth. Up to a 4-fold reduction in interstrand cross-link formation by cis-DDP in resistant compared to sensitive cells was present as measured by alkaline elution. No significant differences were detectable either in the extent of DNA platination as analyzed by atomic absorption spectroscopy or in the induction of cis-DDP DNA adducts as evaluated by an enzyme-linked immunosorbent assay employing antiserum that detects intrastrand cross-links formed by cis-DDP. Further, no differences in the kinetics of excision of DNA interstrand cross-links, cis-DDP DNA adducts, or total platinum in DNA were present. Levels of glutathione, however, were increased about threefold in resistant compared to sensitive cells. Loss of resistance was associated with increased interstrand cross-link formation and declines in glutathione levels. Our results are consistent with a critical role of glutathione in preventing platinum monoadduct rearrangements resulting in lower levels of interstrand cross-links and resistance to cis-DDP in resistant BE cells.