This well established multidisciplinary program, combining scientists trained in immunology, biophysics, biochemistry, cell biology, and clinical pharmacology, will evaluate the antineoplastic and immunomodulatory functions of humans interferons, mismatched double-stranded (ds) RNAs, and various lymphokines including IL-2 and TNF. This approach provides both powerful tools for uncovering mechanisms of cellular transformation and proliferation of human tumors as well as for developing superior diagnostic strategies. Down-regulation (demotion) of human tumor cells via lymphokines allows genetically-defined progressions to occur resulting in terminal differentiation or cell quiescence by modulation of specific growth-regulating genes. To complement biological investigation, those gene products whose expression is altered by lymphokine and dsRNA treatments will be characterized by novel methodologies. Elucidation of the modulated gene products will allow steps in the pharmacologic cascade of biological modifiers to be highly controlled and focused on precise clinical goals. New classes of dsRNA molecules have been structured to trigger selectively the genetic spectrum of endogenous lymphokines and associated intracellular mediators while avoiding host toxicity. Clinically, mismatched analogs of r/n rc/n inhibit proliferation of tumor clones and strengthen immunologic defense against residual tumor even when the tumors are resistant to exogenous interferon. To break further the intrinisc resistance of certain tumors to the interferon effect, novel analogues of 2-5A (nature's antiproliferative pathway) are being developed. Immunomodulatory studies within the multidisciplinary program encompass a broad range of projects from subcellular to organismic levels. Effects of purified lymphokines on normal cell functions, NK and LAC activities, and in athymic mice with tumor xenografts should provide superior clinical rationales. Specific combinations of lymphokines (interferons, dsRNAs, IL-2, etc) will allow for therapeutic synergy by augmentation of selected molecular pathways. Such an in-depth study, brought about by a fully integrated approach, will establish not only new principles for therapy but can also tailor effective therapy for chemotherapy resistant malignancies.
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