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

The antitumor effect of 22-oxa-calcitriol (OCT), a newly developed noncalcemic analogue of calcitriol, was examined /'/; vivo in athymic mice implanted with human breast carcinoma with or without estrogen recep tor (ER). In ER-positive MCF-7 tumor, the growth of which was depen dent 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 ug/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 dosedependent manner without raising serum calcium concentrations. The antitumor effect of 1.0 ug/kg BVVOCT (mean ±SEM of tumor weight in 10 mice: 44 ±6% of vehicle-treated group) was greater than that of 500 ug/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.