NITRIC-OXIDE IS AN IMPORTANT MEDIATOR FOR TUMORICIDAL ACTIVITY IN-VIVO

When cultured in vitro, peritoneal macrophages, obtained from mice previously inoculated with bacillus Calmette-Guerin, release nitric oxide, which is cytostatic and/or cytolytic for tumor cells. However, it is not known whether nitric oxide has antitumor effects in vivo. Here we demonstrate that nitric oxide is an important mediator of host resistance to syngeneic and xenogeneic ovarian tumor grafts in C3HeB/FeJ mice. A murine ovarian teratocarcinoma cell line, utilized to study the mechanism of bacillus Calmett-Guerin-induced host resistance to a syngeneic ovarian tumor, proliferated when transplanted intraperitoneally. Marked tumoricidal activity was observed, however, when these murine ovarian teratocarcinoma cells were transplanted 8 days after intraperitoneal bacillus Calmette-Guerin inoculation. In studies related to xenogeneic ovarian tumor grafts, tumoricidal activity was observed after intraperitoneal transplantation of a human epithelial ovarian cancer cell line, NIH:OVCAR-3. This cell line proliferates only in athymic nude (immunologically incompetent) mice. In both sets of experiments, tumoricidal activity was reduced by inhibition of nitric oxide synthesis. These results demonstrate the tumoricidal action of nitric oxide in vivo.