Circadian dependence of host and tumor responses to cyclophosphamide in mice

Abstract

In a series of five experiments, 505 female BDF 1 mice were standardized for periodicity studies by exposure to alternating periods of 12 hr of light and 12 hr of darkness. The mice were inoculated intraperitoneally with 1 million L1210 murine leukemia cells and beginning approximately 24 hr later, were injected by the same route with a single dose of cyclophosphamide at 1500, 1800, 2100, 0600 or 0900 hr. At each time point, different groups of mice were treated with 300 or 360 mg of cyclophosphamide per kg of body weight. Cured mice ( 60-day survivors) as well as mice dying from drug-induced toxicity or tumor were noted for each interval of treatment. The magnitude of the effects produced by cyclophosphamide varied widely from experiment to experiment, suggesting that factors presently unidentified also influenced host responses to the drug. Nevertheless, the composite data indicated that both the therapeutic and the toxic effects of cyclophosphamide were quantitatively related to the circadian phase of drug administration. The frequency of cures was highest ( 34%) when the drug was administered at 1800 hr and lowest ( 7%) when given at 0900 hr. In addition, drug-induced toxicity exhibited a reverse pattern of cyclic activity in which the minimum value ( 20%) resulted from administration at 1800 hr while the maximum number of deaths ( 52%) occurred after treatment at 0900 hr. Due, in part, to this reciprocal relationship between cure rate and drug-induced death rate, the selective timing of cyclophosphamide administration resulted in greatly divergent modification of the risk versus benefit ratio. As the result of treatment at 0900 hr, approximately 7 mice were killed for each mouse that was cured while, after treatment at 1800 hr, 1.7 mice were cured on the average for each mouse that was killed. Thus by taking advantage of temporal fluctuations in host resistance to cyclophosphamide, enhanced therapeutic responses without equivalent increases in toxicity may be produced.