Interleukin-1 (IL-1), a multifunctional cytokine, induces the synthesis of regulatory molecules which effect endothelial cells, macrophages, T cells and other accessory cells. The applicant has demonstrated previously that IL-la induces acute tumor hemorrhagic necrosis, changes in tumor blood flow and increases clonogenic tumor cell kill. Under support of this grant, they have demonstrated that IL-la significantly enhances cisplatin (cDDP) and carboplatin (CBDCA) anti- tumor activities with time-dependent differences. To minimize toxicity, IL-la was administered by low dose continuous infusion and shown to maintain enhanced CBDCA anti-tumor effects and diminished CBDCA- induced thrombocytopenia. Using a method developed in the applicant's laboratory for the isolation of freshly derived tumor endothelial cells, they have demonstrated that IL-la/ interferon-g (IFN-g) (acytokine induced in the tumor after IL-la) induces a significant level of NO as compared to normal endothelial cells. Tumor-endothelial cells also express increased levels of message for entactin, an extracellular matrix protein. Lastly, IL-la significantly enhanced anti-tumor efficacy of cyclophosphamide (CTX) alone, CTX/CBDCA or CBDCA/etoposide (VP-16).
The aims of this study are: 1) to characterize endothelial cells isolated from untreated and IL-la treated tumor-bearing mice with normal endothelial cells with respect to proliferative response, cellular adhesion molecule (CAM) expression, the ability to synthesize matrix metalloproteinases; 2) to determine whether NO production by tumor-derived endothelial cells contributes to IL-1a induced anti-tumor effects and potentiation of platinum-mediated anti-tumor activities; 3) to determine whether a relationship exists between gene expression of entactin, an extracellular matrix protein, and IL-1a induced effects on tumor endothelium in vitro and in vivo and 4) to examine the ability of IL-la to enhance the therapeutic efficacy of CBDCA in combination with VP-16. These studies will provide the groundwork for the use of IL-1 or related cytokines either alone or in combination with cytotoxic drugs for the therapy of solid tumors.
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