The overall goal of the proposed research is to explore mechanisms of activation and regulation of function in normal and neoplastic cells. The studies involve (a) cytoplasmic control of cell replication, (b) modification of tumor cell properties by non-cytotoxic lymphokines, (c) regulation of lymphokine production and the expression of lymphokine activity, and (d) the effects of non-immunologic growth factors on the immune response. Studies in the first category are based on our observation that mitogen- or interleukin-activated normal lymphocytes contain a cytoplasmic protein (ADR) that can induce DNA synthesis in isolated nuclei in a cell-free system. We have also found that this factor is produced consitutively by neoplastic cells. We propose to investigate this regulatory system for cell proliferation by purifying ADR, studying the mechanisms involved in its reaction with the cell nucleus, and determining the abnormalities of ADR, nucleus, and inhibitory systems in neoplastic cells. Studies in the second category are based on the premise that modification of functional properties of tumor cells by immunologic mediators may be as useful a form of tumor therapy as the more commonly attempted strategies desighed to kill tumor cells. To this end, we are studying the ability of lymphokines to inhibit tumor cell migration and inhibit binding of tumor cells to endothelium, as well as the effects of lymphokines on other aspects of tumor cell behavior. Studies in the last two categories are designed to provide insight into novel ways in which immune regulation may be achieved, with special attention to lymphokine production and the expression of lymphokine activity. To this end, various immunologic regulatory macromolecules as well as hormonal growth and regulatory factors not generally considered to be part of the immune system will be investigated. Our overall approach for this aim involves the purification and characterization of responsible factors, elucidation of their mechanism of action, investigation of possible alterations in neoplastic states, and, ultimately, attempts to manipulate the systems in which they participate for possible therapeutic effort. It is hoped that these studies will provide insights into basic mechanisms of cell growth and regulation.
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