Chronotherapy of mammary cancer in rats

Two studies were performed on female Fischer rats, housed 2/cage with food and water ad libitum in rooms maintained at 24 degrees C and with lights on daily for 8 hours (LD 8:16). In each study 192 rats were innoculated subcutaneously with 13762 mammary adenocarcinoma. Of these, 168 received chemotherapy, separate groups being treated at 1 of 6 different circadian stages. As controls, 24 tumour-bearing rats received saline while 24 rats without tumours received therapy. Chemotherapy consisted of 0.8 mg/kg Adriamycin (ADR) i.p. daily from day 11 to day 19 post tumour inoculation (except for days 16 and 17) followed by 1.6 mg/kg phenylalanine mustard (PAM) p.o. 3 times weekly beginning on day 20. In study-I PAM treatment was continued until 50% of the treated tumour-bearing rats died. In Study-II a 50% overall reduction in mean tumour size was not achieved before regrowth, presumably due to differences in the source of the rats, tumour-heterogeneity and/or other factors. At 50% overall tumour size reduction in the first study there was a statistically significant effect of treatment-timing on tumour size and on percent remission. The greatest reduction in mean tumour size and the highest percentage remission was observed in rats treated at the onset of darkness (activity), a timing similar to that observed in previous studies for optimal tolerance of ADR and PAM by the host. No deaths were observed in treated rats without tumours. When the drug combination used was sufficiently active against the tumour, the therapeutic index (selective toxicity) was improved by timing therapy according to circadian rhythms in the tumour-host system. This effect was achieved with doses not lethal to the nontumourous host. The presumption by others that chronotherapy depends on the use of toxic doses does not here apply.