The ultimate goal of the research proposed in this application is to define potentially useful means by which to therapeutically exploit an anticancer agent's immunomodulating effects in cooperation with its own direct antitumor action and/or that of other therapies.
The specific aims of the research seek to validate in mice the therapeutic advantages of protocols designed to maximize Adriamycin (ADM)-induced biological response modifications without compromising its direct antineoplastic cytolytic activity. The protocols to be evaluated involve treatment with ADM in combination with biological response modifiers (BRMs) selected to complement the known biological effects of ADM. The BRMs selected include interleukin-2 (IL2), interferon gamma, tumor necrosis factor, muramyl tripeptide phosphatidylethanolamine and killer cells expanded in IL2 supplemented cultures. The EL4 tumor/C57BL/6 mouse model has been used to accrue the available information on ADM-induced immunomodulation and will continue to be used to establish parameters for effective combinations. Representative tumor models for validation of promising treatment combinations against neoplasms of particularly clinical interest have been selected and include tumors of the breast, colon, kidney and ovary. The conditions which will be evaluated include single dose vs. multidose, timing of administration of various agents, and local vs systemic treatment. In each case attempts will be made to correlate tumor reduction with biological response modification. The biological responses which will be evaluated are specific cytotoxic T lymphocytes, lymphokine activated killers, natural killers, tumoricidal macrophages, production of cytokines (IL1, IL2, TNF, IFN-gamma and PGE2), and tumor induced suppression (i.e. both suppressor cells and soluble suppressive factors). Finally, studies will be initiated to consider whether anticancer agents induce changes in the regulatory bidirectional circuitry that purportedly links the immune and neuroendocrine systems. The acheivement of the goals of this research is dependent upon demonstrating a clear therapeutic advantage of protocols designed to maximize not only the antiproliferative but also the immunomodulating properties of an anticancer drug. Such a demonstration should provide a unique contribution to the design of clinical protocols for evaluation of chemo-immunotherapies.
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