The multidisciplinary programs, combining scientists trained in cell biology, biochemistry, immunology, pharmacology, and viral oncology will evaluate the antineoplastic, immunomodulatory, and antiviral functions of human interferon. The human interferon system can provide a powerful tool for uncovering mechanisms of cellular transformation and proliferation of tumor cells. Our objectives include elucidating mechanisms whereby interferon can phenotypically correct tumor cells by forcing their entry into differentiation programs. Down-regulation or demotion of tumor cells via interferon should allow genetically defined progressions to occur, resulting in either terminal differentiation or cell quiescence. Interferon may play a role in normal development/ differentiation and unlock specific genes. To complement biological investigation, recombinant DNA technology will reveal those specific sets of genes whose expression is altered during differentiation and malignant transformation. The approach depends upon an in-depth study of interferon action at various levels of biological organization: in tissue culture and athymic mice and in patients with neoplastic disease. Also, new classes of interferon inducers have been structured to trigger the various forms of endogenous interferon without host toxicity. Mismatched analogs of rIn.rCn can strengthen immunological defense to tumor. Immunomodulatory studies of interferon and its inducers will encompass a broad range of projects from subcellular to organismic levels. Effects of interferon on lymphocyte functions, including natural killer cells and macrophage activity, should provide a firm clinical rationale for its improved use in pharmacological modulation of neoplasia. The antiproliferative limb of interferon action will be systematically determined following transplantation of human tumor cells, particularly those of epithelial origin, into athymic mice. Such an innovative and in-depth study brought about by a fully integrated approach will establish earlier diagnostic methods and new principles for effective biological therapy of cancer, thus resulting in more effective control and elimination of cancer cells in humans. (V)
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