The overall goal of this project is to define mechanisms involved in the antitumor activity of human recombinant IL-1 in RIF-1 and Panc02 murine tumor models, and to investigate new approaches to solid tumor therapy by combining IL-1 and chemotherapy. Clonogenic cell survival and regrowth delay endpoints will be used to determine dose and time dependent IL-1 mediated tumor cytotoxicity. Since IL-1 is not cytotoxic to RIF-1 cells, in continuous culture, in vivo cytotoxicity is likely mediated by tumor host cells. This hypothesis will be tested in studies to define the role of tumor macrophages and their products (e.g. TNF) in IL-1 mediated tumor cell kill in vivo. IL-1 mediated vascular and proliferative responses could influence the effectiveness of other therapeutic modalities in solid tumors. Time and dose response studies will be conducted to determine the effects of IL-1 on blood flow, vascular patency tumor pH and water distribution in tumor and normal tissues by isotope dilution methods. The regulatory role of adrenal hormones and prostaglandins, in IL-1 mediated vascular responses, and the importance of reduced tumor blood flow and tumor pH, in IL-1 mediated cytotoxicity, will be studied. Since IL-1 might be used with other modalities, the effect of immunosuppressive therapy (chemotherapy, surgery) on IL-1 antitumor activity will be determined. The information from these experiments will be used to design therapeutic strategies in which chemotherapy (Cp, Adr, liposome encapsulated Adr) is applied to exploit IL-1 mediated antitumor activities. These strategies will be tested in RIF-1 and Panc02 tumors, using clonogenic cell survival and regrowth delay endpoints. The results from these studies will provide the conceptual framework for the use of IL-1, as a single agent and in combination with chemotherapy and surgery, to improve the management of human malignancies.
