EFFECTIVENESS AND TOXICITY OF PROTRACTED NITRIC-OXIDE SYNTHESIS INHIBITION DURING IL-2 TREATMENT OF MICE

The current study was designed to characterize nitric oxide (NO .) syn thesis 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 inhib itor N-omega monomethyl-L-arginine (MLA) via osmotic minipump to aid i n further study of these processes. After IL-2 administration to C3H/H eN 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 mu M/mouse/day ), and normal mice (from 1 to 0.5 mu M/mouse/day). This agent decrease d IL-2-induced radiolabeled albumin accumulation in the liver after i. p. IL-2 administration (p < 0.02). MLA infusions resulted in minimal s ystemic toxicity in mice, as reflected by complete blood counts or ser um chemistries. MLA also did not impair lymphokine-activated killer ce ll induction in vitro or in vivo, or alter IL-2-induced tumor response s in a 3-day pulmonary metastasis model. These experiments demonstrate d that NO . is a mediator involved in the genesis of vascular permeabi lity induced by IL-2 treatment. Studies designed to further evaluate t he toxicity and usefulness of MLA infusions to modify this IL-2 induce d toxicity appear to be warranted.