Induction of differences in the circadian profiles of DNA synthesis between normal and neoplastic cell populations by hydroxyurea without perturbation of the normal circadian rhythms.

This paper presents data which support a previously stated hypothesis that differences in phasing can be induced in the rhythms of DNA synthetic activity (DNA-SA) between normal and neoplastic cell populations in the same animal. The drug used was hydroxyurea (HU). Mice were standardized to a light-dark cycle with light from 06.00 to 18.00 h. Minimal disruption of the normal circadian pattern in DNA-SA in tongue, esophagus, and rectum occurred when 500 mg/kg HU was given at 17.00 h. The same dose of HU given at 05.00 h resulted in significant perturbation of the normal circadian pattern of DNA-SA in these organs. 500 mg/kg HU at 17.00 h did, however, significantly perturb DNA-SA in the Ehrlich's ascites cardinoma (EAC). To study this phenomenon further the following experiments were done in EAC bearing mice: (A) 500 mg/kg HU given at 09.00, 13.00 and 17.00 h; (B) 500 mg/kg HU given at 21.00, 01.00 and 05.00 h, and (C) 3,000 mg/kg given at 17.00 h. In general, the response of the normal organs to HU varied depending on the circadian time of treatment with HU, whereas the response of the EAC was more uniform regardless of when the HU was given. By plotting the data obtained from the 3 normal organs and the EAC on the same graph specific points could be identified when: (a) maximal DNA-SA occurred in the EAC and at the same time minimal DNA-SA occurred in tongue, esophagus, and rectum, or (b) various levels of DNA-SA occurred in the EAC, but, at the same time maximal or peak levels of DNA-SA occurred in the normal organs.