The objectives of the proposed research are to develop therapeutic drug regimens that will have use in the treatment of cancer in man on the basis of pharmacological and biochemical information on the mechanism of drug action, and fundamental information in processes in neoplastic cells that may be considered cellular sites of vulnerability. To accomplish these objectives, this application will use the induction of terminal differentiation of neoplastic cells by chemical and/or biological agents as a therapeutic approach to the treatment of cancer. To achieve these goals the specific aims are: (a) to characterize the role of the lipocortins and eicosanoids in the maturation of squamous carcinoma and leukemia cells; (b) to determine cytosketal changes during the transition from the immature cell to the mature state; (c) to study the mechanism of induction of leukemia cell differentiation by anthracyclines; (d) to develop and employ in vivo systems to determine the therapeutic effectiveness of differentiation inducing agents; (e) to evaluate the role of fos and jun oncogenes in leukemia cell maturation; and (f) to study the mechanism of signal transduction by erythropoietin in erythroleukemia cells. It is anticipated that information will be obtained which will provide significant leads that will ultimately result in the development of approaches with clinical utility that function to produce therapeutic benefit in cancer patients by the induction of the terminal differentiation of neoplastic cells, as well as provide information on factors involved in the regulation of malignant cell growth and differentiation.
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