Effectiveness and Toxicity of Protracted Nitric Oxide Synthesis Inhibition During IL-2 Treatment of Mice

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Abstract
Summary: The current study was designed to characterize nitric oxide (NO-) synthesis during interleukin-2 (IL-2) treatment of mice, and to determine whether NO- mediated IL-2-induced “vascular leak.” We developed a technique for chronic subcutaneous infusion of the NO- synthase inhibitor N™ monomethyl-L-arginine (MLA) via osmotic minipump to aid in further study of these processes. After IL-2 administration to C3H/HeN mice (180,000 IU i.p. b.i.d. for 5 days), NO- synthesis increased two-to-three fold, peaking on days 5-8. Administration of MLA reduced NO- synthesis in both IL-2-treated mice (from 2.7 to 1 μ.M/mouse/day), and normal mice (from 1 to 0.5 μM/mouse/day). This agent decreased IL-2-induced radiolabeled albumin accumulation in the liver after i.p. IL-2 administration (p<0.02). MLA infusions resulted in minimal systemic toxicity in mice, as reflected by complete blood counts or serum chemistries. MLA also did not impair lymphokine-activated killer cell induction in vitro or in vivo, or alter IL-2-induced tumor responses in a 3-day pulmonary metastasis model. These experiments demonstrated that NO- is a mediator involved in the genesis of vascular permeability induced by IL-2 treatment. Studies designed to further evaluate the toxicity and usefulness of MLA infusions to modify this IL-2 induced toxicity appear to be warranted.

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