ANTITUMOR EFFECT OF 22-OXA-CALCITRIOL, A NONCALCEMIC ANALOG OF CALCITRIOL, IN ATHYMIC MICE IMPLANTED WITH HUMAN BREAST-CARCINOMA AND ITS SYNERGISM WITH TAMOXIFEN

The antitumor effect of 22-oxa-calcitriol (OCT), a newly developed non calcemic analogue of calcitriol, was examined in vivo in athymic mice implanted with human breast carcinoma with or without estrogen recepto r (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 antie strogen tamoxifen five times a week for 4 weeks suppressed tumor growt h in a dose-related fashion. The antitumor effect of 1.0 mug/kg body w eight (BW) OCT (mean +/- SEM of tumor weight in 6 mice: 28 +/- 4% of v ehicle-treated group) was comparable to that of 2.0 mg/kg BW tamoxifen (25 +/- 6% of control group). In addition, a synergistic antitumor ef fect of submaximal doses of OCT and tamoxifen was observed in MCF-7 tu mor 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 wee k 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 mug/kg BW OCT (mean +/- SEM of tumor weigh t in 10 mice: 44 +/- 6% of vehicle-treated group) was greater than tha t of 500 pg/kg BW Adriamycin (71 +/- 6% of control group). These resul ts indicate that OCT suppresses the growth of ER-negative as well as E R-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 system ic adjuvant therapy of breast carcinoma regardless of ER status.