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Abstract
Grant Number: 1R43CA099849-01 PI Name: SOUTHAN, GARRY J. PI Email: gjsouthan@aol.com PI Title: Project Title: Novel anti-oxidant catalyst to treat IL-2 toxicity Abstract: DESCRIPTION (provided by applicant): IL-2 biotherapy of refractory malignancies may produce cardiovascular toxicities and hemodynamic alterations that are indistinguishable from those seen in septic shock. These host responses include a massive capillary leak syndrome, manifested as non-cardiogenic pulmonary edema and consequent respiratory failure. There is now substantial evidence that the inflammatory process to IL-2 biotherapy is mediated by profound alterations in the biosynthesis of the free radicals nitric oxide and superoxide anion, and their reaction product peroxynitrite. An effective anti-inflammatory treatment would reduce the toxicity of IL-2 treatment and encourage increased use of this highly promising antineoplastic therapy. To address this unmet need, Inotek is developing a novel class of ultrapotent peroxynitrite decomposition catalysts. The lead compound, the metalloporphyrin INO-1080, is dramatically protective in experimental models of systemic inflammatory shock. The investigators propose to establish "proof-of-principle" that INO-1080 reduces the hemodynamic biochemical, and histopathologic alterations in an experimental model of IL-2 biotherapy. First, the investigators will ensure that INO-1080 does not adversely impact the anti-tumor activity of IL-2. They will carry out these investigations in a murine model of pulmonary metastasis by syngeneic melanoma cells. Second, they will document in a large animal model that INO-1080 ameliorates shock and tissue injury induced by IL-2. The investigators will utilize a well-established ovine model of IL-2 induced shock. The investigators expect INO-1080 will reduce tissue injury, capillary leak, pulmonary hypertension, lipid peroxidation, and nitrotyrosine formation, and attenuate the loss of systemic vascular resistance. Confirmation of efficacy, coupled with evidence that INO-1080 does not adversely impact on the anti-tumor activity of IL-2, would justify clinical testing in population with refractory malignant melanoma.
Thesaurus Terms:
antiinflammatory agent, antioxidant, catalyst, drug adverse effect, drug design /synthesis /production, immunotherapy, interleukin 2, metalloporphyrin
combination chemotherapy, hemodynamics, nitric oxide, peroxynitrite
histopathology, laboratory mouse, sheep
Institution: INOTEK PHARMACEUTICALS CORPORATION 100 CUMMINGS CTR, STE 419E BEVERLY, MA 01915 Fiscal Year: 2003 Department: Project Start: 14-MAR-2003 Project End: 29-FEB-2004 ICD: NATIONAL CANCER INSTITUTE IRG: ZRG1