The effect of 5-fluorouracil at elevated temperatures on a spontaneous mouse tumour: Arrhenius analysis and tumour response.

Abstract

In a series of studies to investigate activation energies and thermal enhancements of various chemotherapeutic agents the effect of 5-fluoruracil (5FU), an antimetabolite, on murine tumour cells was studied at elevated temperatures. Animal tumours were early generation isotransplants of a spontaneous fibrosarcoma, FSa-II tumours, and C3Hf/Sed mice were used throughout. Cell survival curves for 5FU were obtained as a function of treatment time by in vitro treatment-in vivo lung colony assay at temperatures between 37.0 and 43.5 degrees C. The D0, or the treatment time to reduce surviving fraction from S to S/e in the exponential portion of the survival curve, decreased slightly from 37 degrees C treatment to 41.5 degrees C treatment. The D0 decreased substantially from 41.5 degrees C to 43.5 degrees C. Arrhenius-plot analysis indicated that the activation energies were 92.9 and 731 kJ/M at temperatures between 37 and 41.5 degrees C, and between 41.5 and 43.5 degrees C, respectively. The activation energy of 92.9 kJ/M for the temperature range from 37 to 41.5 degrees C was the lowest of the other agents, bleomycin, cis-diamminedichloroplatinum and 1,3-bis(2-chloroethyl)-N-nitrosourea, which have been investigated in our laboratory. This indicated that the thermal enhancement was smallest among these agents. In vivo experiments failed to demonstrate thermal enhancement of the anti-tumour effect of 5FU. Namely, combined 5FU and heat treatments at 41.5 and 43.5 degrees C did not prolong the tumour growth time compared with 5FU given at room temperature. No pH effect was found in an in vitro experiment and glucose administration did not enhance the anti-tumour effect of 5FU.