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Antiproliferative Activity of -Interferon Combined with Lipopolysaccharide on Murine Adenocarcinoma: Dependence on an L-Arginine Metabolism with Production of Nitrite and Citrulline¹

U. A. 1116, Institut de Biochimie, Université de Paris-Sud, Orsay, France

Growth of the murine adenocarcinoma EMT6 was moderately inhibited by up to 32 units/ml of -interferon (IFN-). However, EMT6 growth was blocked by as low as 2 U/ml of IFN-, when added with lipopolysaccharide. In the same time, the combination IFN- + lipopolysaccharide induced synergistically the production of nitrite and citrulline by EMT6 cells. Synthesis of the two products was correlated with IFN- concentrations. It required exogenous L-arginine and was inhibited by a methylated L-arginine derivative, N^G-monomethyl-L-arginine. Inhibition was specific since urea synthesis was not reduced by N^G-monomethyl-L-arginine. The L-arginine-dependent pathway was involved in EMT6 cytostasis mediated by IFN- + lipopolysaccharide because cytostasis expression required L-arginine and was inhibited by N^G-monomethyl-L-arginine.

¹ This work was supported by CNRS UA 1116, INSERM C.R.E. 853007, and la Ligue Nationale Française contre le Cancer.

² To whom requests for reprints should be addressed, at Institut de Biochimie, Bât.432, Université de Paris-Sud, 91405 Orsay Cedex, France.

Received 7/12/88. Revised 11/15/88. Accepted 1/16/89.