Differential cytotoxicity and DNA cross-linking in normal and transformed human fibroblasts treated with cis-diamminedichloroplatinum(II).
DNA interstrand cross-linking had been found previously to correlate with differences in sensitivity among human cell strains treated with chloroethylnitrosoureas. These differences had been attributed to the presence or absence of a specific DNA repair mechanism. The current work addressed the question of whether another DNA cross-linking agent, cis-diamminedichloroplatinum(II) (cis-Pt), would exhibit analogous differences between cell types. A normal human embryo cell strain (IMR-90) was compared with an SV40-transformed line (VA-13). Interstrand cross-linking and DNA-protein cross-linking were assayed by alkaline elution. As in the case of chloroethylnitrosoureas, the cytotoxicity differences with cis-Pt correlated with differences in interstrand cross-linking. The relative sensitivity of the cell lines to cis-Pt, however, was reversed. Similar DNA-protein cross-linking levels in the two cell lines excluded a difference in cis-Pt uptake or intracellular metabolic drug activation or inactivation prior to DNA interaction. It was concluded that the DNA repair mechanism that prevents interstrand cross-linking by chloroethylnitrosoureas does not prevent interstrand cross-linking by cis-Pt. Interstrand cross-linking by cis-Pt may be prevented by an independent mechanism.
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D003114:Colony-Forming Units Assay; D003432:Cross-Linking Reagents; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D006801:Humans
D003432:Cross-Linking Reagents; D004247:DNA; D002945:Cisplatin