Time‐dependent toxicity of drugs used in cancer chemotherapy: Separate and combined administration

Time‐dependent toxicity of 3 anti‐cancer drugs was demonstrated in BALB/c mice. Cisplatinum, adriamycin and cyclophosphamide were injected at 4 different circadian stages, either together (combined injection) or separately, to different groups of mice. Toxicity was evaluated by body‐weight changes, mortality and white blood cell counts. Maximal body‐weight loss was caused by the administration of either Cisplatinum or the combination of all 3 drugs at 15.00 hr and 21.00 hr, i.e., 9 and 15 hr after fight on (HALO). Only moderate body weight loss was induced when adriamycin was injected at 09.00 hr or at 21.00 hr (3 and 15 HALO). In contrast to Cisplatinum and adriamycin, cyclophosphamide induced no significant change in body weight when injected at either time. The highest level of mortality was caused by the injection of all 3 drugs together at 21.00 hr (15 HALO). No death occurred when drugs were administered separately. The rate of recovery (as assessed by weight regain) also exhibited dependence upon the time of drug administration and was the slowest after injections at 21.00 hr (15 HALO). It appears, therefore, that the time‐dependence modes of toxicity and recovery (as assessed by body‐weight change) are different. The decrease in white blood cell count also exhibited a time‐dependence pattern which differed from that of weight loss and death.