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Angiogenesis Inhibitor TNP-470 Inhibits Human Breast Cancer Osteolytic Bone Metastasis in Nude Mice through the Reduction of Bone Resorption¹

Department of Oral and Maxillo-Facial Surgery II, Okayama University Dental School, Okayama 700 [A. S., R. E. A., A. N., D. D. L., H. M., T. M.], and Department of Tumor Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537 [H. A.], Japan

Angiogenesis inhibitor TNP-470, 6-O-(N-chloroacetyl-carbamoyl)-fumagillol, semisynthetic analogue of fumagillin, has strong inhibitory activities against in vivo tumor growth and metastasis in a wide variety of tumors. However, it is still unknown whether this agent inhibits bone metastasis. We examined the effects of TNP-470 in a bone metastasis model in nude mice in which intracardiac injection of the human breast cancer cell line MDA-MB-231 (MDA-231) produced osteolytic bone metastasis. After inoculation of MDA-231 cells into the left heart ventricle, TNP-470 (30 mg/kg, three times a week) or PBS was s.c. administrated for 4 weeks. After this period, the TNP-470 had reduced not only the number and area of osteolytic bone metastases (approximately 60 and 70%, respectively) but also their radiolucency. Histological examination of the femurs of the untreated group revealed that most of the cancellous bone had been replaced by the metastatic cancer. Numerous active osteoclasts were present along the trabecular bone surface surrounded by the metastatic MDA-231 cancer cells aggressively invading the bone marrow. In contrast, in the bone from TNP-470-treated mice, bone destruction was markedly inhibited, and there were much fewer osteoclasts. In a murine bone marrow culture under 1,25-dihydroxyvitamin D₃ in which mature functional osteoclasts formed in vitro, TNP-470 significantly inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated osteoclast-like cells. And also, TNP-470 suppressed the in vivo bone resorption in calvaria treated with interleukin-1ß, an osteoclast stimulator. These data suggested that TNP-470 inhibited bone metastasis through not only antitumor action by its angiogenesis inhibition but also by the inhibition of osteoclastic bone resorption. Our results indicate that TNP-470 should be a potentially beneficial drug to be used in the treatment of osteolytic metastasis.

¹ This work was supported by Grants-in-Aid for the Second Term Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health and Welfare and in part by Grant 09672049 for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan.

² To whom requests for reprints should be addressed, at Department of Oral and Maxillofacial Surgery II, Okayama University Dental School, 2-5-1 Shikata-Cho, Okayama 700, Japan. Phone: 81-86235-6702; Fax: 81-86235-6704; E-mail: aksasaki@dent.okayama-u.ac.jp.

Received 8/14/97. Accepted 12/ 3/97.

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