Chronobiology is the study of biological rhythms. There are a number of chronobiological effects which may have important clinical implications for antitumor therapies. For example, chronobiological effects on the replication of some types of tumor cells, the expression of certain drug toxicities, and the number of cytotoxic effector cells have been described. Interferon therapies are currently being evaluated in clinical trials for their potential as antitumor agents. This proposal focuses on possible chronobiological effects which may effect the potencies of various interferon therapies. We propose to evaluate the chronobiological effects on tumor growth of interferons administered (1) as single agent therapy; (2) as multiple interferon therapies (IFN-gamma plus IFN-alpha or IFN- beta); (3) as multiple agent therapies with hyperthermia; and, as multiple agent therapies with phenytoin. These studies will be performed both in vitro, using B-16 melanoma cells in cloning studies, and in vivo, using the B-16 melanoma/C57/B1/6 tumor system. Simultaneous treatments and various sequential treatments will be compared to identify the most potent treatment protocol. We also propose to evaluate the chronobiological effects on IFN-mediated bone marrow suppression of colony stimulating factor administration. These studies will be performed both in vitro using bone marrow colony growth assays and in vivo using total white blood cell counts as an indicator of bone marrow suppression.
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