N-G-NITRO-L-ARGININE METHYL-ESTER INHIBITS BONE METASTASIS AFTER MODIFIED INTRACARDIAC INJECTION OF HUMAN BREAST-CANCER CELLS IN A NUDE-MOUSE MODEL

We investigated the effects of N-G-nitro-L-arginine-methyl ester (L-NA ME), a nitric oxide synthase (NOS) inhibitor, on bone metastasis of hu man breast cancer, MDA-231 cells. Tumor cells (2 X 10(5) cells in 0.2 mi of phosphate-buffered saline; PBS) were injected through the diaphr agm into the left ventricle of the heart of laparotomized nude mice (m ale 5-week-old ICR-nu/nu). L-NAME (2 mg/mouse/injection in 0.1 ml of P BS) was given intraperitoneally to mice 6 h and 3 h before and immedia tely, 3 h, 6 h, 18 h and 21 h after the intracardiac injection of tumo r cells. As a control, 0.1 mi of PBS was injected instead of L-NAME. T he effect of N-G-nitro-D-arginine-methyl ester (D-NAME; 2 mg/mouse/inj ection), an inactive analogue of L-NAME, was also investigated to eval uate the specificity of L-NAME action. Radiographical examination 31 d ays after the tumor-cell injection showed that the incidence and numbe r of osteolytic bone metastases and the number of bones with metastasi s in L-NAME-treated mice were significantly reduced compared with thos e in PBS-treated mice (P<0.05). The differences between PBS-treated an d D-NAME-treated mice were not significant. Our findings suggest that specific and appropriate NOS inhibitors may represent a new pharmacolo gical approach to therapy for cancer patients at risk of developing os teolytic bone metastases.