The effect of cis-diamminedichloroplatinum(II) treatment at elevated temperatures on murine fibrosarcoma, FSa-II

Abstract

The effect of cis-diamminedichloroplatinum(II) (cis-DDP) on the murine fibrosarcoma cells was investigated in vitro and in vivo. For in vitro experiments tumour cell suspensions containing a given amount of cis-DDP were treated in water bath maintained at a desired temperature, and cell survival was determined by the lung colony assay. The D₀ or the time to reduce survival from 1 0 to 0–37 on the exponential portion of the survival curve was determined and 1/D₀ was plotted as a function of 1/T, where T stands for the absolute temperature. The slope of this Arrhenius plot indicated that the activation energy for chemical reaction of cis-DDP was 44 kcal/M between the temperature range from 37 to 41°C. For in vivo experiments tumours were transplanted into the foot and treated by immersing the animal foot into a water bath when each tumour reached an average diameter of 4 mm (35 mm³). The drug was injected i.p. immediately before hypothermia. The tumour growth (TG) time or the time required for a tumour to reach 1000 mm³ from the treatment day was determined, and the median TG time was obtained by logit analysis. Dose-response curves between the TG time and drug dose indicated that the cytotoxic effect of cis-DDP was enhanced at elevated temperatures. This enhancement increased with increasing temperature from room temperature to 43·5°C. Because of short plasma half-time of cis-DDP, continuous infusion and pulse injections were attempted. A significant enhancement was observed following pulse injections, but continuous infusion failed to enhance the effect of this agent at 41·5°C. It might be a unique feature of cis-DDP that the effect of cis-DDP administered immediately prior to or immediately following hyperthermia was equally enhanced. These results suggests that cis-DDP is a potential agent which can be used at elevated temperatures.