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, cytotoxicity, mutagenicity, and antitumor activity.
Several effects of four diamminechloroplatinum compounds (II and IV) in Chinese hamster ovary cells were studied. The two cis-compounds [cis-diamminedichloroplatinum(II) and cis-diamminetetrachloroplatinum(IV)] are known to possess antitumor activity, whereas the two trans-stereoisomers [trans-diamminedichloroplatinum(II) and trans-diamminetetrachloroplatinum(IV)] are inactive. When the effects of the cis-and trans-platinum compounds were compared after treatments that resulted in the binding of equal amounts of platinum to the DNA of the cells, the following differences were found: (a) the cis-platinum adducts gave a much higher cytotoxicity; (b) only the cis-platinum-DNA complexes were strongly mutagenic (forward mutations at the hypoxanthine-guanine phosphoribosyltransferase locus); (c) the cis-platinum adducts induced more sister chromatid exchanges; (d) the cis compounds initially induced fewer DNA-protein cross-links (Factors 5 to 8), but these cis-platinum cross-links were much more persistent; (e) for both cis complexes, the amount of DNA interstrand cross-links passed through a maximum between 6 and 12 hr 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 platinum-DNA lesions as such nor the initial amount of DNA interstrand cross-links could be related to the (geno)toxic effects of the compounds. However, as the slow repair of the cis-platinum-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-platinum-DNA adducts. The sister chromatid exchange induction seems to be related to the persistent DNA interstrand cross-links.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000633:toxicity*; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D005260:Female; D007700:Kinetics; D009153:Mutagens; D009154:Mutation; D010053:Ovary; D011485:Protein Binding; D012854:Sister Chromatid Exchange / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D009153:Mutagens; C034697:transplatin; C041149:diamminetetrachloroplatinum(II); D004247:DNA; D002945:Cisplatin