Certain anticancer agents have been shown to induce selective modulating effects on immune responses and there may be therapeutically exploitable host responses against certain neoplasms. Therefore, it can be proposed that protocols which optimize a drug's therapeutically favorable immunomodulating effects without unduely compromising its direct antitumor toxicity may maximize its antineoplastic potential. The goal of this research project is to obtain verification, in murine models, that imbalances of antitumor host defenses induced by an anticancer drug are therapeutically exploitable. The ultimate goal of this area of research is to define potentially clinically useful means by which to therapeutically exploit an anticancer agent's immunomodulating effects in cooperation with its own antitumor effects or that of other therapies. The further studies of four selected Adriamycin-induced changes, which appear to have potential therapeutic utility are among the immediate goals of this research project. These changes are: 1) increased """"""""IL-2 like"""""""" activity; 2) elimination of adherent T-regulatory cell activity; 3) augmented cytotoxic T-lymphocyte activity; 4) an increase in a population of immature macrophages. The purification and identification of the IL-2 like factor (with authentic IL-2) will be accomplished by HPLC techniques. The enrichment and further characterization of the adherent T-regulatory cell will utilize monoclonal antibodies in affinity chromatography and surface antigenic marker identification. The possible contribution of these two changes to the total ADM-induced effects on antitumor defenses in the syngeneic tumor bearing host model will be determined. Host defenses will be assessed according to effects on various functions including phagocytosis, cytolysis of target cells, tumor growth inhibition, suppression of responses. The experimental verification that one or more of these four selected Adriamycin-induced changes are therapeutically advantageous will be sought by evaluating their in vivo antitumor effects by adoptive or passive transfer into mice bearing selected syngeneic tumors. This proposed research is related to the possibility of deliberately using anticancer drugs not only as antiproliferative but also as immunomodulating agents. Such a demonstration should contribute to the design of a clinically applicable approach, which is different from that pursued by other laboratories concerned with immunotherapy and thus provides a measure of uniqueness to this program.
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