The antitumor effects of
cyclophosphamide were previously shown to be markedly reduced by the application of restraint stress in mice bearing
Lewis lung carcinoma. The aim of this work was to determine the effects of rotational stress on the antitumor action of
cyclophosphamide in the same animal-
tumor system. Since the effects of rotational stress on
metastasis were found to display a circannual rhythm, with a maximum in summer and a minimum in winter, the experiments were performed in June and February. Groups of 10 young female mice were kept under low stress housing conditions, with a 12-12 h light/dark cycle, starting 2 weeks before and during each experiment. Rotational stress caused an increase of
metastasis volume to 361% of nonstressed controls in June and a decrease to 32.4% in February. In both seasons, the treatment with
cyclophosphamide (240 mg/kg/day for 6 days) caused the absence of detectable
metastasis at sacrifice in all mice; its combination with rotational stress caused the presence of
metastases in similar proportions (6/10 and 10/10 for June vs February, respectively). The survival time of control mice was approximately twice as long in February as in June and was not appreciably modified by rotational stress;
cyclophosphamide was similarly active in both seasons (4/10 and 6/10 long-term survivors for June vs February, respectively), and the number of long-term survivors was reduced to 0/10 in both seasons by rotational stress. The survival of the different experimental groups inversely correlated with the number of
metastases as determined at sacrifice at the end of treatment and also with the number of CD3(+) and CD4(+) splenic T-lymphocyte subsets. These results do not appear to depend on the disruption of the circadian organization of the mice by rotational stress or by seasonal differences in
cyclophosphamide activity. On the other hand, they can be interpreted assuming that
cyclophosphamide reduces
tumor metastasis and that T-lymphocyte-mediated immune responses of the host, amenable to modulation by stress and displaying seasonal differences uncoupled from circadian rhythms, further contribute to the
tumor inhibitory effects of the drug. The observed differences in
tumor metastasis caused by rotational stress and survival time in two different seasons, and the marked attenuation of
cyclophosphamide antitumor action by rotational stress, appear of interest for their experimental and clinical implications.