Effects of temperature on the interaction of cisplatin and carboplatin with cellular DNA.
Increased levels of cisplatin (cDDP)- and carboplatin (CBDCA)-DNA adducts were detected in cDDP (10 microM)- and CBDCA (6 mM)-treated CC531 cells when the temperature was raised from 37 degrees to 43 degrees. In the case of cDDP, increased DNA adduct formation was already detectable at 38.5 degrees; additional temperature steps led to further increases in DNA modification. Increased CBDCA-DNA adduct formation was observed only at temperatures higher than 40 degrees. In vitro studies on the interaction of CDDP and CBDCA with isolated salmon sperm DNA, however, demonstrated no significant differences in the DNA binding rate between 37 degrees and 43 degrees for cDDP and a minor effect for CBDCA only at 43 degrees, almost totally excluding a direct temperature effect on DNA platination in this temperature range. Furthermore, neither the stability of the formed platinum-DNA adducts nor the rate of adduct loss in CC531 cells was changed at higher temperatures. The observed difference in cellular adduct formation, however, could be related to increased uptake of cDDP and CBDCA into CC531 cells at higher temperatures. In the case of cDDP, a temperature shift from 37 degrees to 38.5 degrees resulted in a significantly higher intracellular platinum concentration (0.03 +/- 0.01 vs 0.071 +/- 0.021 micrograms platinum/10(6) cells, respectively); for CBDCA, temperatures > or = 41.5 degrees were needed to increase the platinum concentration significantly above 37 degree values (0.3 +/- 0.1 vs 0.6 +/- 0.1 micrograms platinum/10(6) cells, respectively). In addition, the increase in DNA adduct formation of cDDP and CBDCA at elevated temperatures was comparable with the increase in cDDP-DNA adducts after a cDDP concentration escalation at 37 degrees, indicating a concentration-dependent increase in cDDP-DNA adducts. It seems that heat affects primarily the cellular uptake of cDDP and CBDCA and not their covalent binding to DNA.
Los
G
G
Division of Experimental Chemotherapy, The Netherlands Cancer Institute, Amsterdam.
van Vugt
M J
MJ
den Engelse
L
L
Pinedo
H M
HM
D000818:Animals; D016190:Carboplatin / Q000378:metabolism* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism* / Q000494:pharmacology; D004247:DNA / Q000032:analysis / Q000378:metabolism*; D018736:DNA Adducts; D004305:Dose-Response Relationship, Drug; D006358:Hot Temperature; D010984:Platinum / Q000032:analysis; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018736:DNA Adducts; C057270:cisplatin-DNA adduct; D010984:Platinum; D004247:DNA; D016190:Carboplatin; D002945:Cisplatin