N^G‐Nitro‐L‐arginine Methyl Ester Inhibits Bone Metastasis after Modified Intracardiac Injection of Human Breast Cancer Cells in a Nude Mouse Model

Abstract

We investigated the effects of N G ‐nitro‐L‐arginine‐methyI ester (L‐NAME), a nitric oxide synthase (NOS) inhibitor, on hone metastasis of human breast cancer, MDA‐231 cells. Tumor cells (2 × 10 5 cells in 0.2 ml of phosphate‐buffered saline; PBS) were injected through the diaphragm into the left ventricle of the heart of laparotomized nude mice (male 5‐week‐old ICR‐ nu/nu ). L‐NAME (2 mg/ mouse/injection in 0.1 ml of PBS) was given intraperitoneally to mice 6 h and 3 h before and immediately, 3 h, 6 h, 18 h and 21 h after the intraeardlac injection of tumor cells. As a control, 0.1 ml of PBS was injected instead of L‐NAME. The effect of N G ‐nitro‐D‐arginine‐methyl ester CD‐NAME; 2 mg/mouse/injection), an inactive analogue of L‐NAME, was also investigated to evaluate the specificity of L‐NAME action. Radiographical examination 31 days after the tumor‐cell injection showed that the incidence and number of osteolytic bone metastases and the number of bones with metastasis in L‐NAME‐treated mice were significantly reduced compared with those in PBS‐treated mice (P<0,05). The differences between PBS‐treated and D‐NAME‐treated mice were not significant. Our findings suggest that specific and appropriate NOS inhibitors may represent a new pharmacological approach to therapy for cancer patients at risk of developing osteolytic bone metastases.