INVERSE CORRELATION BETWEEN EXPRESSION OF INDUCIBLE NITRIC-OXIDE SYNTHASE ACTIVITY AND PRODUCTION OF METASTASIS IN K-1735 MURINE MELANOMA-CELLS

The purpose of these studies was to determine whether the induction of NO synthase activity in murine K-1735 melanoma cells correlated with their metastatic potential. Nonmetastatic, metastatic, and somatic cel l hybrids (produced by fusion of nonmetastatic and metastatic cells) w ere injected i.v. into syngeneic C3H/HeN mice. Metastatic cells surviv ed to produce experimental lung metastases, whereas nonmetastatic cell s did not. The various clones and somatic cell hybrids were incubated in vitro with combinations of tumor necrosis factor, interleukin 1, ga mma-interferon, and lipopolysaccharide. Nonmetastatic cells exhibited high levels of inducible NO synthase activity and NO, whereas metastat ic cells did not. Both the cytotoxic effects of the cytokines and NO p roduction were inhibited by the addition of N(G)-monomethyl-L-arginine , a specific inhibitor of NO synthase. These data demonstrate an inver se correlation between production of endogenous NO and the ability of K-1735 cells to survive in syngeneic mice to produce lung metastases.