Expression of inducible nitric oxide synthase in tumors in relation with their regression induced by lipid A in rats

It is well documented that nitric oxide (NO) is an effector molecule of mac rophage-mediated tumor cell toxicity in vitro; however, little is known abo ut the role of NO in the antitumor immune response in vivo. We have develop ed a treatment protocol using lipid A. We have investigated the effects of lipid A on inducible NO synthase (NOS II) expression and evolution inside t umors during the course of treatment. Lipid A (OM-174) treatment induced tu mor regression in rats bearing established colon tumors. Furthermore, NO wa s synthesized and secreted inside the tumors of lipid A-treated rats, as de monstrated by the increase of NOS II mRNA and NOS II content in the tumors, as well as of NOS II activity and NO production. During treatment, NOS II was localized in tumor cells only. Lipid A had no direct effect on tumor ce lls in vitro, while the combination of interferon gamma (IFN-gamma) plus in terleukin-l beta (IL-1 beta) induced production of NO by tumor cells which was cytostatic, The content of IFN-gamma and IL-1 beta in tumors was enhanc ed during lipid A treatment; this is in agreement with an indirect effect o f lipid A in vivo via the IFN-gamma and IL-1 beta pathways. (C) 1999 Wiley- Liss.