The overall goal of this study is to determine whether the cytokine interleukin-1 (IL-1) can be used to increase the therapeutic efficacy of chemotherapeutic agents. IL-1, a product of the cells of the macrophage/monocyte series, is a multifunctional cytokine that potentiates hematopoiesis, induces the synthesis of CSF in vitro and in vivo, and plays a central role in T and B cell activation. Data from our laboratory demonstrate that treatment of normal mice with IL-1 causes significant neutrophilia, increases serum CSF levels, increases number of granulocyte and macrophage progenitor cells, suppresses erythroid progenitor cells, and hastens myeloid recovery following cyclophosphamide (CP) treatment. We have also found that IL-1 alone causes acute hemorrhagic necrosis of solid tumors in vivo and significantly reduces tumor blood flow, clonogenic cell viability and proliferation. Thus, IL-1 has the potential to substantially increase the therapeutic index of cytotoxic drugs by reducing their dose- limiting myelosuppression, by permitting higher or more frequent administration of chemotherapeutic agents, and by enhancing the anti-timor effects of the drugs. This will be directly and systematically tested in the well-characterized RIF-1 model system through the following specific aims: 1) to establish the optimum effective dose of IL-1, to determine the ability of this dose to increase the maximum tolerated dose of cyclophosphamide in normal and tumor-bearing animals, and to characterize the effect of this therapy on hematopoiesis; 2) to determine whether the combination of IL-1 and high dose cyclophosphamide possesses greater anti-tumor effects than conventional doses of cyclophosphamide alone; 3) to determine whether IL-1 enhances the anti-tumor effects of cytotoxic drug therapy by augmenting immunological reactivity against the tumor, stimulating production of other cytokines or affecting tumor vascular physiology; and, 4) to determine whether the addition of specific cytokines to the combination therapy with Il-1 and cyclophosphamide will improve the hematopoietic and anti- tumor effects. The results of this study could provide the groundwork for use of cytokines in combination with cytotoxic drugs to improve the treatment of human malignancies.
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