The overall objective of this research program is to further our understanding of the molecular and cellular basis for the antitumor action of pure natural and recombinant human interferon (IFN)-alpha, beta, and gamma, either alone or in combination with each other, or with other antitumor agents such as tamoxifen or DFMO. Our approach at the molecular level will be to use two-dimensional gel electrophoresis and computer-based quantitative densitometry on a Leitz Tas Plus Image Analyzer to examine the protein profile, i.e., the proteins produced or altered in synthetic rates in IFN-treated, freshly explanted, purified human tumor cells or tumor cell lines. At the cellular level we will examine the effect of IFN on tumor cell proliferation and on surface antigen expression by the tumor cells, tumor-associated lymphocytes, and macrophages. We will also study the effects of IFN on lymphocyte-tumor and macrophage-tumor cell interactions that occur in a ?51?Cr cytotoxic assay and in an agarose tumor colony assay. Thus, we can determine whether for a given patient or tumor type, IFN expresses its antiproliferative effects on cells of the immune system as well as directly on the tumor. Solid or ascitic fluid samples of ovarian, breast, and gastric carcinoma will be evaluated, as well as established lines of carcinoma of the lung (A549), kidney (CRL 1611), ovary (HOC-1), breast (MCF-7) and cervix (HeLa), myeloma (8226), erythroleukemia (K562), and malignant gliomas. The results should provide a biochemical basis for the differential responsiveneas to IFN of patients with the same tumor, or for one malignancy versus another, as well as providing definite insights into the question of synergy among the IFNs, and whether high or low dose therapy is preferable for a particular tumor. Given the known amino acid sequence of all the IFNs, our studies should provide considerable information on the relationship of a given IFN to its functions and biologic profile, and also help point out the significance of the IFN-induced peptides. This knowledge will be of benefit to those clinicians who design and perform IFN clinical trials, with regard to defining the maximum therapeutic potential and strategy of administration of each IFN. These experiments will also serve as a model for similar ones with other biologic response modifiers. (HF)
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