title: 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.
abstract: 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.
mesh_terms: 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
chemical_list: D000903:Antibiotics, Antineoplastic; D009153:Mutagens; C034697:transplatin; C041149:diamminetetrachloroplatinum(II); D004247:DNA; D002945:Cisplatin