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Antitumor Effect of 22-Oxa-calcitriol, a Noncalcemic Analogue of Calcitriol, in Athymic Mice Implanted with Human Breast Carcinoma and Its Synergism with Tamoxifen¹

Research Laboratories, Chugai Pharmaceutical Co., Ltd., Tokyo 171 [J. A-H., Y. N.], and Division of Endocrinology, Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo 112 [T. K., T. M., E. O., K. I.], Japan

The antitumor effect of 22-oxa-calcitriol (OCT), a newly developed noncalcemic analogue of calcitriol, was examined in vivo in athymic mice implanted with human breast carcinoma with or without estrogen receptor (ER). In ER-positive MCF-7 tumor, the growth of which was dependent on exogenous estrogen, administration p.o. of OCT as well as the antiestrogen tamoxifen five times a week for 4 weeks suppressed tumor growth in a dose-related fashion. The antitumor effect of 1.0 µg/kg body weight (BW) OCT (mean ± SEM of tumor weight in 6 mice: 28 ± 4% of vehicle-treated group) was comparable to that of 2.0 mg/kg BW tamoxifen (25 ± 6% of control group). In addition, a synergistic antitumor effect of submaximal doses of OCT and tamoxifen was observed in MCF-7 tumor in vivo as well as in ER-positive breast carcinoma cell lines (MCF-7 and ZR-75-1) in vitro. Administration of OCT p.o. three times a week for 4 weeks also suppressed the growth of ER-negative MX-1 tumor in a dose-dependent manner without raising serum calcium concentrations. The antitumor effect of 1.0 µg/kg BW OCT (mean ± SEM of tumor weight in 10 mice: 44 ± 6% of vehicle-treated group) was greater than that of 500 µg/kg BW Adriamycin (71 ± 6% of control group). These results indicate that OCT suppresses the growth of ER-negative as well as ER-positive breast carcinoma in vivo without causing hypercalcemia and that the antitumor effect of OCT can be enhanced by tamoxifen in an ER-positive tumor. It is suggested that OCT may provide a new strategy, either alone or in combination with other anticancer drugs, for systemic adjuvant therapy of breast carcinoma regardless of ER status.

¹ Supported in part by Grants-in-Aid for Encouragement of Young Scientists (K. I.) and for Scientific Research (T. M.) from the Ministry of Education, Science and Culture of Japan and grants from the Japan Research Foundation for Clinical Pharmacology (K. I.) and from Uehara Memorial Foundation (K. I.).

² Present address: Cancer Institute, Tokyo 170, Japan.

³ To whom requests for reprints should be addressed, at Division of Endocrinology, Fourth Department of Internal Medicine, University of Tokyo School of Medicine, 3-28-6 Mejirodai, Bunkyo-ku Tokyo 112, Japan.

Received 12/30/92. Accepted 3/26/93.

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