NITRIC-OXIDE IS AN EFFECTOR MOLECULE IN INHIBITION OF TUMOR-CELL GROWTH BY RIFN-GAMMA-ACTIVATED RAT NEUTROPHILS

This study was designed to determine the effector molecule responsible for the tumor-inhibitory activity of rat neutrophils treated with rat recombinant interferon gamma (rIFN-gamma) in vitro. The results show that nitric oxide (NO) production by neutrophils is dependent on rIFN- gamma concentration, and that neutrophil-mediated tumor cytostasis is in turn dependent on the amount of NO. NO production and tumor cytosta sis by rIFN-gamma-activated neutrophils were inhibited completely by N -G monomethyl-L-arginine (N(G)MMA), a specific competitive NO producti on inhibitor. Tumor cytostasis was also inhibited by oxyhemoglobin (Hb O(2)), an WO scavenger. An extracellular oxygen radical scavenger, sup eroxide dismutase (SOD), was found to increase tumor cell inhibition b y rIFN-gamma-activated neutrophils by a factor of 4. This SOD-enhanced cytostasis was not even inhibited by catalase. Tumor cytostasis was s lightly increased by a hydroxyl radical (. OH) scavenger, dimethylthio urea (DMTU), which did not affect NO production by rIFN-gamma-activate d neutrophils. Our findings suggest that tumor cytostasis of neutrophi ls activated by rIFN-gamma is mediated by L-arginine-derived nitrogen oxidation products, and that O-2(-) produced by these neutrophils redu ces NO-mediated tumor cytostasis at low NO concentrations. (C) 1997 Wi ley-Liss, Inc.