It is proposed to investigate the circadian stage dependency of the toxicities, biologic activities and anticancer activities of recombinant human Tumor Necrosis Factor (rhTNF) and Interleukin 2 (rhIL-2) in the Balb/c mouse with and without an implanted Meth-A sarcoma. We have found preliminarily that the circadian time and season of tumor inoculation affect both tumor take rate and natural killer cell activity. We have also found that the timing of tumor resection within the fertility cycle affects the frequency of subsequent metastatic tumor spread and that the fertility cycle affects the level of immunocyte NK activity. Therefore, the effects of female fertility cycle stage and season at time of study will also be quantified. The biological effects of most, if not all, trophic hormones are dependent to some extent upon the temporal patterning of their release or administra- tion. Fertility depends upon the pulsatility of FSH and LH delivery from the pituitary to the ovary and testis. Cortisol release depends intimately upon both the high frequency pulsing and the circadian patterning of ACTH delivery from the pituitary to the adrenal glands. IL-1 is a centrally positioned cytokine having synergistic activities with TNF and interactive or stimulatory effects upon several other cytokines and growth factors. Glucocorticoids (which are exquisitely circadian rhythmic) modulate the dynamics of IL-1 gene transcription rate, messenger RNA stability and resultant translation rate and IL-1 cellular release rate, as well as TNF- induced cytotoxicity. IL-1, in turn, modulates glucocorticoid receptor binding, decreases available binding sites and reduces steroid-associated enzyme induction. These steroid/cytokine interactions suggest that chronobiologic investigation of cytokine toxicity and anticancer efficacy may be important. The toxic and therapeutic anticancer effects of many cytotoxic xenobiotic anticancer agents depend upon their circadian timing. Reproducible peak- trough circadian differences in toxicity and anticancer activity usually range between 50% and 250%. Preliminary data on tumor necrosis factor indicate that the circadian stage dependent differences in toxic/therapeut- ic ratio may be of substantially higher magnitude for cytokines. Specific hypotheses to be addressed by the proposed research include: 1) Endogenous, reproducible, nontrivial and quantifiable circadian rhythms ( which are reproducibly modulated by both the fertility cycle and season) characterize (murine and human) normal biology; 2) Population synchrony, gauged by reference to sleep-wake schedules and physiologic circadian marker rhythms, may be used to extrapolate phase relationships appropriate- ly from individual and species to species; 3) Endogenous activity of natural immunologic defense networks have rhythmic circadian, fertility cycle and seasonal variation; 4) The hypophyseal-adrenal network is an important circadian coordinator of cellular immune networks; 5) These networks have rhythmic circadian, fertility cycle and seasonal variation in their ability to be stimulated; 6) The circadian timing of TNF reproducibly affects its toxicity and its antitumor efficacy; 7) The circadian timing of IL-2 reproducibly affects its toxicity and its antitumor efficacy.
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