A group of recently described guanylhydrazone compounds inhibit macrophage activation through multiplicative inhibition of production of specific pro-inflammatory cytokines (TNF, IL-1beta, IL-6, MIP-1alpha, MIP-1beta) and nitric oxide (NO). The lead compound, CNI-1493, is extremely effective in multiple preclinical models of endotoxic shock, adult respiratory shock syndrome (ARDS), sepsis, pancreatitis, experimental allergic encephalomyelitis (EAE), stroke, arthritis and colitis. In Sprague Dawley rats with subcapsular established Novikoff hepatomas which were treated with continuous IL-2, CNI-1493 treatment completely prevented the IL-2 mediated normal tissue toxicities and associated deaths and allowed for a dose of at least 10-fold more IL-2 to be delivered. Most importantly, CNI-1493 had no deleterious effect on IL-2 mediated tumor killing, and in fact may have augmented the IL-2 response. This project will extend testing of CNI-1493 in the hepatoma model, including development of pharmacokinetic assays, toxicity studies, and an understanding of its structure activity relationship. Differential mechanisms of IL-2 normal cell vs. tumor cell toxicity will be studied in situ by apoptosis and immunohistochemical staining. Finally, additional murine models of IL-2 toxicity and anti- tumor activity will be evaluated to confirm the increased activity and therapeutic window. Results form this Phase I will be used to support clinical trial testing and eventually commercial development of CNI-1493 as a dose modifying agent for IL-2 treatment of selected cancers.
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