INDUCTION AND REPAIR OF DNA CROSS-LINKS IN CHINESE-HAMSTER OVARY CELLS TREATED WITH VARIOUS PLATINUM COORDINATION-COMPOUNDS IN RELATION TO PLATINUM BINDING TO DNA, CYTO-TOXICITY, MUTAGENICITY, AND ANTITUMOR-ACTIVITY

  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (5) , 2043-2051
Abstract
Several effects of 4 diamminechloroplatinum compounds (II and IV) in Chinese hamster ovary cells were studied. The 2 cis-compounds [cis-diamminedichloroplatinum(II) and cis-diamminetetrachloroplatinum(IV)] possess antitumor activity, whereas the 2 trans-stereoisomers [trans-diamminedichloroplatinum(II) and trans-diamminetetrachloroplatinum(IV)] are inactive. When the effects of the cis- and trans-Pt compounds were compared after treatments that resulted in the binding of equal amounts of Pt to the DNA of the cells, the following differences were found: the cis Pt adducts gave a much higher cytotoxicity; only the cis-Pt-DNA complexes were strongly mutagenic (forward mutations at the hypoxanthine-quanine phosphoribosyltransferase locus); the cis-Pt adducts induced more sister chromatid exchanges; the cis compounds initially induced fewer DNA-protein cross-links (Factors 5-8), but these cis-Pt cross-links were much more persistent; for both cis complexes, the amount of DNA interstrand cross-links passed through a maximum between 6 and 12 h after treatment and the cross-links were repaired slowly. One trans-compound [trans-diamminetetrachloroplatinum(IV)] resembled the cis complexes with respect to the overall kinetics of formation and disappearance of this type of lesion, but the repair went faster. For the other trans compound [trans-diamminedichloroplatinum(II)], the highest number of cross-links was detected directly after the treatment of the cells and they were rapidly eliminated. Neither the number of Pt-DNA lesions as such nor the initial amount of DNA interstrand cross-links could be related to (geno)toxic effects of the compounds. As the slow repair of the cis-Pt-induced interstrand and DNA-protein cross-links leads to a certain persistency of these adducts, the unrepaired lesions might be responsible for cytotoxicity, mutagenicity and antitumor activity. This indicates discriminating properties of the repair systems for certain cis- or trans-Pt-DNA adducts. The sister chromatid exchange induction seems to be related to the persistent DNA interstrand cross-links.