Circadian rhythms in DNA synthesis and mitosis in normal mice and mice bearing the Lewis lung carcinoma.
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Biomedical subjects
Publications and source records attributed to L E Scheving.
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Epidermal growth factor (EGF) previously isolated from the submandibular gland of mice was injected ip at different circadian phases into separate subgroups of adult male CD2F1 mice. Subsequent to each of the five time points of injection (0900, 1500, 1800, 2100, and 0300 h for animals standardized to 12 h of light alternating with 12 h of darkness), five animals were killed, 4, 8, and 12 h after the injection of EGF; comparable control groups were injected only with the carrier substance. Thirty minutes before sacrifice, each mouse was injected ip with 24 muCi [3H]thymidine. Incorporation of [3H]-thymidine into the DNA of the tongue, esophagus, and stomach was determined. The results demonstrate for the first time that EGF has a strong in vivo stimulatory effect on DNA synthesis in the tongue, esophagus, and stomach (studies on other areas of the gut have not yet been completed). Under the conditions of the study, stimulatory effects occurred as soon as 4 h subsequent to injection; however, maximal stimulation occurred for all three tissues 8 h after injection. Twelve hours after injection, the levels of DNA synthesis in all tissues were generally returning to normal levels found in the control animals. The results suggest circadian variation in susceptibility to EGF in the different tissues.
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Under the conditions of disynchronization by the manipulation of both the alternation of light and darkness and the availability and unavailability of food, circadian rhythms characterize the excretion of several amino acids by inbred LOU rats bearing an immunocytoma. Large amplitude rhythms can be demonstrated for urinary beta-aminoisobutyric acid, beta-alanine, phenylalanine and tyrosine. Under the same conditions of disynchronization, control animals excrete the same compounds also with a marked circadian variation but at an invariably lower average rate. These excretory rhythms, along with those demonstrated earlier for polyamines and light-chains, are of interest as potential markers for the chronotherapy of cancer.
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Non-specific immunostimulation with Bacillus Calmette-Guérin (BCG) is of current interest in the treatment of cancer. The main objective of the series of experiments described in this paper was to evaluate the influence the host's circadian system has on a. the stimulation of the immune system with BCG and b. the subsequent efficiency of that stimulated immune system against the Ehrlich Ascites Carcinoma (EAC). There was a circadian rhythm in the length of survival time in non-immunized mice challenged with the EAC. Mice receiving an EAC challenge during the middle of the light period survived significantly longer than those challenged with the EAC around the time of transition from dark to light. Mice immunized with BCG and challenged with EAC also demonstrated a circadian rhythm in the length of survival 30 days after EAC challenge with 86% survivors in the mice treated at 10(00) and 60% survivors in the mice treated at 07(00). The same relationship was also observed 70 and 80 days after EAC challenge. Eighty days after EAC challenge, a circadian rhythm was apparent in the frequency of solid tumors at the site of the initial EAC injection. The highest incidence of solid tumors occurred at 13(00). A circadian rhythm was found in the increase in body weight between the first and second BCG or saline injections. Rectal temperatures recorded on the 8th, 12th and 16th day after EAC challenge were characterized by circadian rhythmicity. In the mice without development of ascites, the peak temperature consistently occurred at 01(00). In the mice with ascites there was a phase advance in the rectal temperature rhythm of 3 h so that the peak in the rhythm consistently occurred at 22(00). In the mice with ascites a further finding was an increasing hypothermia as the ascites continued to develop; however, this hypothermia was not detectable during the time of the peak (10(00)) in the temperature rhythm. The mice which did not die by the 80th day after EAC challenge were challenged again with 5.0 x 10(6) EAC cells, and during the next 46 days circadian variations were observed in the numbers of mice which survived. Similar changes were observed during an additional 46 days after a third EAC challenge of 41.5 x 10(6) cells.
In cancer and other therapeutic research, an interpretation of median survival times can and should take cure into account. With this qualification, an analysis of recently published data provides further statistically significant evidence in favor of cancer chronotherapy as compared to homeostatic therapy.
Some emotional disorders are associated with alterations of biological rhythm characteristics ('echronism'). Chronotherapy aims empirically to 1. optimize the kind and timing of conventional psychopharmacologic treatment and, need be, to use such old or new molecules in the rational endeavor to 2. correct (disease-determining) rhythm alteration directly. With respect to the first aim, a reduction by timing of undesired pharmacodynamic effects, as well as an amplification of empirically desired ones, can be dramatically illustrated by circadian rhythms in tolerance to many drugs affecting the central nervous system of rodents. A more rational approach is aimed at correcting ecchronism. The new antidepressant drug, nomifensine, achieves this task in rats with bilateral suprachiasmatic lesions, exhibiting in the telemetered core temperature an echronism of varying degrees. In this model system for the chronobiotic treatment of ecchronism, the properly timed administration of nomifensine speeds the adjustment of bilaterally (suprachiasmatically) lesioned rats to a shift in the synchronizing light-dark schedule. With methodologic provisions, notably for treatment timed by pertinent marker rhythms, nomifensine deserves clinical tests in psychochronotherapy.