Effects of N(G)-Nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, on IL-2-induced LAK cell generation in vivo and in vitro in healthy and tumor-bearing mice.
We had earlier shown that therapy with N(G)-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 cytotoxicity in vivo and in vitro in splenocytes of healthy and C3-L5 tumor-bearing C3H/HeJ mice, using 51Cr release assay. IL-2 treatment, in vivo or in 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 production in vivo and improved IL-2-induced splenocyte cytotoxicity as well as tumor regression. Addition of L-NAME in vitro also 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 production in vivo causes 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.
Orucevic
A
A
Department of Anatomy, University of Western Ontario, London, Canada.
Lala
P K
PK
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007376:Interleukin-2 / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000276:immunology*; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D007376:Interleukin-2; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester