Circadian Rhythmicity in DNA Synthesis in Untreated and Saline-treated Mice as a Basis for Improved Chronochemotherapy

Abstract

DNA-synthetic activity (DNA-SA) was measured by liquid scintillation counting of the incorporation of tritiated thymidine into chemically isolated DNA from the tongue, stomach, terminal ileum, rectum, spleen, and bone marrow in mice standardized to a 12-hr light-12-hr dark cycle with light from 6 a.m. to 6 p.m. Central Standard Time. One group of 200 mice was not treated or not touched (NT). A second group of 200 mice was given an injection of 0.9% NaCl solution (SAL) at 5 a.m. Beginning at 8 a.m., or 3 hr after treatment with SAL, 10 mice from both the NT and SAL groups were killed every 3 hr for 60 hr. Statistically significant circadian rhythms in DNA-SA were found in all organs in the NT group when the data were analyzed by the single-cosinor rhythmometric method. The amount of statistical error encountered in fitting a 24-hr cosine curve to the original data was smallest in tongue and progressively increased in stomach, rectum, spleen, ileum, and bone marrow. An explanation for this finding is presented which involves the histokinetic architecture of these organs. Treatment with SAL at 5 a.m. abolished the circadian rhythms in DNA-SA in spleen, bone marrow, and ileum, increased the overall level of DNA-SA in the rectum, and decreased the overall level of DNA-SA in ileum and spleen. The circadian rhythmicity of DNA-SA in all of the organs studied in the NT group, in general, attained peak activity sometime during the nocturnal period (active phase for mice). Trough levels of DNA-SA occurred during the diurnal or rest period. This observation is correlated with the known circadian rhythms in susceptibility-resistance to drugs which primarily or exclusively effect DNA-SA; i.e., the circadian rhythms in mortality to these drugs attain peak levels during the nocturnal period. This informaton forms the basis for a hypothesis which states that the most therapeutically advantageous situation would be to induce a significant circadian phase difference in the rhythms in DNA-SA between the normal and the neoplastic cell populations of a tumor-bearing host. Anti-DNA-SA therapy could then be given at a specific point in time when DNA-SA of the host was at or near trough levels and, concomitantly, DNA-SA of the tumor was at or near peak levels. This should result in maximal or selective toxicity to the tumor and, concomitantly, minimal toxicity or maximal protection of the normal tissues of the host.