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Prolonged Decrease of Serum Calcium Concentration by Murine -Interferon in Hypercalcemic, Human Tumor (EC-GI)-bearing Nude Mice¹

Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical College, Kawada-cho 8-1, Tokyo 162 [K. Sa., H. D.]; Research Institute for Growth Science in Japan Wakamatsu-cho 9-4, Shinjuku-ku, Tokyo 162 [T. S., K. Sh., Y. Y.]; Experimental Technology Research Center, Research Institute, Daiichi Pharmaceutical Co., Kitakasai 1-16-13, Edogawa-ku, Tokyo 134 [Y. O.]; and Department of Biochemistry, School of Dentistry, Showa University, Hatanodai 1-5-8, Shinagawa-ku, Tokyo 142 [T. A., N. T., T. S.], Japan

Murine -interferon (MuIFN-) is a potent inhibitor of bone resorption induced by interleukin 1 and parathyroid hormone-related protein in vitro. To investigate whether MuIFN- is also effective in vivo, the cytokine was injected s.c. into hypercalcemic, tumor (EC-GI)-bearing nude mice, in which parathyroid hormone-related protein and interleukin 1 are synergistically responsible for causing humoral hypercalcemia.

When MuIFN- was injected s.c. at a dose of 1 to 20 x 10⁴ units for 5 days consecutively, serum calcium concentrations in the tumor-bearing mice decreased in a dose-dependent manner. The minimal effective dose was 5 x 10⁴ units/mouse. Unlike calcitonin, which decreased the serum calcium concentration for only 1 to 2 days despite continuous daily injections, MuIFN- decreased it for more than 7 days even after the injections had been stopped. Human -interferon was completely ineffective. The decrease in serum calcium concentration was accompanied by a decrease in urinary calcium excretion. Histological examination of the femur revealed a decreased number of osteoclasts in the MuIFN--treated mice. Furthermore, MuIFN-, when injected into nude mice or normal mice at a dose of 15 x 10⁴ units for 3 days, almost completely abolished the formation of multinucleated osteoclast-like cells in vitro.

These findings suggest that MuIFN- suppresses the formation and maturation of osteoclasts and inhibits osteoclastic bone resorption, resulting in the prolonged decrease of serum calcium concentration seen in hypercalcemic, tumor-bearing nude mice. Therefore, bone resorption inhibitors like MuIFN-, which ameliorate humoral hypercalcemia without an escape phenomenon, are potentially useful for the treatment of malignancy-associated hypercalcemia.

¹ This Work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (02671109) and by a Grant-in-Aid for Cancer Research (1–33) from the Ministry of Health and Welfare of Japan. Part of this work was presented at the 49th Annual Meeting of the Japan Cancer Society, Sapporo, Japan, July 1990, and at the 12th Annual Meeting of the American Society for Bone and Mineral Research, Atlanta, GA, August 1990 (Abstract 484).

² To whom requests for reprints should be addressed, at Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical College, Kawadacho 8-1, Shinjuku-ku, Tokyo 162, Japan.

Received 4/12/91. Accepted 10/28/91.

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