Ultraviolet irradiation produces cytotoxic synergy and increased DNA interstrand crosslinking with cis- and trans-diamminedichloroplatinum(II).
There is indirect evidence to suggest that the excision-repair mechanism responsible for the removal of UV-induced thymine dimers may also play a role in the repair of cis-diamminedichloroplatinum(II) (cis-DDP)-induced DNA adducts in both bacteria and mammalian cells. It was hypothesized that UV dimers and cis-DDP adducts, when present simultaneously, might compete for a common repair system. Colony survival assays were performed in HT-29 human colon carcinoma cells exposed either to cis-DDP alone or to cis-DDP immediately followed by UV exposure. Progressively greater cytotoxic synergy with both increasing UV dose and cis-DDP dose was observed, to a point of saturation beyond which further toxicity was purely additive. Alkaline elution analyses for DNA interstrand crosslinking were performed 6 h after exposure. An approximate doubling in crosslink frequency, relative to cis-DDP alone, was found in cells exposed to cis-DDP plus UV (P = 0.002). Since cis-DDP produces both inter- and intrastrand DNA crosslinks similar studies were performed with trans-DDP, which is incapable of producing intrastrand crosslinks, but does produce interstrand crosslinks. Cytotoxic synergy and increased interstrand crosslinking again resulted from the addition of UV exposure, but not to the same extent as seen with cis-DDP. These data support the hypothesis that cis-DDP induced DNA adducts are, at least in part, removed by an excision-repair mechanism. The similar but quantitatively smaller effects with trans-DDP suggest that intrastrand crosslink removal may also occur by this mechanism.
Swinnen
L J
LJ
Department of Medicine, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153.
Fisher
S G
SG
Erickson
L C
LC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D003110:Colonic Neoplasms; D004261:DNA Replication / Q000187:drug effects / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D006801:Humans; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism; D051379:Mice; D013936:Thymidine / Q000378:metabolism; D014466:Ultraviolet Rays
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C034697:transplatin; D002945:Cisplatin; D013936:Thymidine