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

Abstract

The effect of cis-diamminedichroIoplatinum (II) (cis-DDP) and hyperthermia on cultured Chinese hamster ovary (CHO) cells were investigated. Cells were treated with 6 μM cis-DDP for various durations of time at temperatures ranging from 37 to 43°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 μM cis-DDP) yielded activation energies of 61 kcal/M between 37 and 41°C and 213 kcal/M between 41 and 43°C. Further experiments using two different drug concentrations (3 and 12 μM) confirmed these activation energies in these two different temperature ranges. However, the activation energy for 12 μM cis-DDP given in the temperature range 33–37°C was 22 kcal/M, which is smaller than those found above 37°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°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°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°C, it suggests that the activation energy is identical to that for hyperthermia alone.