Effects ofNG-Nitro-L-arginine Methyl Ester, an Inhibitor of Nitric Oxide Synthesis, on IL-2-Induced LAK Cell Generationin Vivoandin Vitroin Healthy and Tumor-Bearing Mice

Abstract

We had earlier shown that therapy withNG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, had antitumor and antimetastatic effects in C3-L5 mammary adenocarcinoma-bearing mice. When combined with interleukin-2 (IL-2) therapy, L-NAME augmented antitumor effects of IL-2. In the present study, we tested whether the L-NAME effects were due, at least in part, to a potentiation of antitumor cytotoxicity of host effector cells. We examined the effects of L-NAME on IL-2-induced generation of antitumor cytotoxicityin vivoandin vitroin splenocytes of healthy and C3-L5 tumor-bearing C3H/HeJ mice, using51Cr release assay. IL-2 treatment,in vivoorin vitro,markedly stimulated splenocyte tumoricidal activity against NK-sensitive (YAC-1) and -resistant (C3-L5) targets, accompanied with an increase in NO production measured in the serum or culture medium. Addition of L-NAME to IL-2 therapy blocked IL-2-induced NO productionin vivoand improved IL-2-induced splenocyte cytotoxicity as well as tumor regression. Addition of L-NAMEin vitroalso reduced IL-2-induced NO production in the medium and enhanced IL-2-induced cytotoxicity of splenocytes of healthy but not tumor-bearing mice. These results reveal that IL-2-induced increase in NO productionin vivocauses a suppression of LAK cell activation, which can be overcome by NO inhibition with L-NAME therapy. These findings, combined with our observation that L-NAME can mitigate IL-2-induced capillary leakage in healthy and tumor-bearing mice, suggest that L-NAME could be a valuable adjunct to IL-2 therapy of cancer and infectious diseases.