DNA CROSS-LINKING AND CYTO-TOXICITY INDUCED BY CIS-DIAMMINEDICHLOROPLATINUM(II) IN HUMAN NORMAL AND TUMOR-CELL LINES

Abstract

The cytotoxicity and DNA cross-linking induced by cis-diamminedichloroplatinum(II) (cis-Pt) were studied in normal [embryonic lung IMR90 cells], a SV 40-transformed [VA13] and 8 tumor cell lines of human origin [A549 lung carcinoma, A2182 lung carcinoma, A172 astrocytoma (Grade IV), HT29 colon carcinoma, A1336 ovarian carcinoma, BE colon carcinoma, HT1080 fibrosarcoma, and A875 melanoma]. These cell strains were chosen on the basis of their Mer phenotype, i.e., their ability to repair DNA containing 6O-alkylated guanine. The cytotoxicity was assayed by measuring the inhibition of cell proliferation after a 2 h treatment of the cell cultures with cis-Pt concentrations ranging from 1-50 .mu.M. DNA-protein cross-links and DNA interstrand cross-links were measured by DNA alkaline elution after a 2 h treatment with 10 or 20 .mu.M cis-Pt. The different cell lines differed in sensitivity to cis-Pt. The drug concentration required to produce the same inhibition of growth varied over a 10-fold range. Cell sensitivity correlated with DNA interstrand cross-linking (r = 0.83; P < 0.01) better than with DNA-protein cross-linking (r = 0.75; P < 0.05). There was no correlation between cell sensitivity or DNA interstrand cross-linking and the Mer phenotype. The lack of relationship between the extent of DNA interstrand cross-linking by cis-PT and the Mer phenotype suggests that this repair mechanism does not remove from DNA cis-Pt monoadducts that have the potential to form interstrand cross-links.