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

Abstract

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 Ehrlichias 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.

Circadian Biological Time Influences the Effect Adriamycin Has on DNA Synthesis in Mouse Bone Marrow, Ileum and Tongue but not Ehrlich Ascites Carcinoma

“…These are the same conclusions reached in a large study of the effect of single or multiple treatments with HU in this tumor-host sys tem [3]. This lack of the effect of the time of treatment is an interesting property of this and perhaps other tumors.…”

“…This goal, however, has been reached in this tumor-host system with hydroxyurea (F1U) [3] and 5-fluorouraciI [4]. It remains to be seen if a lower dose of ADR would have been more appropriate.…”

“…The original objective was to use ADR to induce major quantitative differences in DNA-SA (a cir cadian phase desynchronization) between normal and neoplastic cell populations in the same animal at some point or period in time with maximal DNA-SA oc curring in the neoplastic cell population and, conco mitantly, minimal DNA-SA in the normal cell popula tions [2][3][4], Since the EAC was quite susceptible to 10 mg/kg ADR and did not reach high levels of DNA-SA during the 60 h after treatment, the goal was not obtained. This goal, however, has been reached in this tumor-host system with hydroxyurea (F1U) [3] and 5-fluorouraciI [4].…”

“…Low levels of DNA-SA were not reached until + 18 h after treatment. In fact, and in contrast to the ADR at 05.00 h data, DNA-SA in the ADR at 17.00 h group rose to a peak level at + 9 h (02.00 h) after treatment; 02.00 h is the normal time for peak DNA-SA in this tissue [2,3], DNA-SA then decreased to low levels from +18 (11.00 hi to +27 (20.00 h). There after.…”

“…Optimization of cancer chemotherapeutic agents to the circadian biology of the normal tissues in the tumor-bearing host has resulted in less toxicity and improved cure rates in both experimental animal [13,15] and human clinical situations [7,8,14], One way to improve on this type of chronochemotherapy might be to induce large, quantitative differences in DNA synthetic activity (DNA-SA) between normal and neoplastic cell populations at the same point in time [2], This circadian phase desynchronization of DNA-SA between normal and neoplastic cells has been accomplished by treating mice bearing the Ehrlich ascites carcinoma (EAC) with hydroxyurea [3] or 5-fluorouracil [4]. This paper reports an attempt to use adriamycin (ADR) to induce differences in DNA-SA between some normal tissues (bone marrow, ileum and epith elium of the tongue) and the EAC.…”