The cytotoxic effect of cis-diamminedichloroplatinum(II) on cultured Chinese hamster ovary cells at elevated temperatures: Arrhenius plot analysis

Abstract

The effect of cis-diamminedichroloplatinum (II) (cis-DDP) and hyperthermia on cultured Chinese hamster ovary (CHO) cells were investigated. Cells were treated with 6 microM cis-DDP for various durations of time at temperatures ranging from 37 to 43 degrees C, and cell survival curves were determined as a function of treatment time. The cytotoxic effect of cis-DDP increased with increasing temperatures, indicating that hyperthermia enhanced cytotoxicity of cis-DDP. Arrhenius analysis of surviving fraction data (6 microM cis-DDP) yielded activation energies of 61 kcal/M between 37 and 41 degrees C and 213 kcal/M between 41 and 43 degrees C. Further experiments using two different drug concentrations (3 and 12 microM) confirmed these activation energies in these two different temperature ranges. However, the activation energy for 12 microM cis-DDP given in the temperature range 33-37 degrees C was 22 kcal/M, which is smaller than those found above 37 degrees C. This activation energy appeared to be identical to that reported for the degradation or depurination of DNA. The activation energy between 37 and 41 degrees C, i.e. approximately 61 kcal/M, was twice as great as that found for alkylation of thio-TEPA, an alkylating agent. This may indicate that the mechanism of action of cis-DDP differs from that of thio-TEPA. A greater activation energy observed in the range of 41-43 degrees C is most likely attributable to the additive effect of hyperthermia and thermal enhancement for cis-DDP. Although only one data point is available at the temperature above 43 degrees C, it suggests that the activation energy is identical to that for hyperthermia alone.