Potentiation of the antitumor effect of tamoxifen by combination with the antiprogestin onapristone.

The present study was undertaken to investigate the antitumor effect of a combination of the antiestrogen tamoxifen (TAM) and either the antiprogestin onapristone (ON) or the progestogen megestrol acetate (MEG) in experimental mammary tumor models. Rats bearing DMBA- or NMU-induced mammary tumors were treated with ON or MEG either alone or in combination with TAM for four weeks. In the DMBA-tumor model, treatment with ON or TAM alone caused tumor remissions, whereas the combination of ON and TAM was almost as effective as ovariectomy (100% remission) and led to a remission of 86-100%. The combination of TAM and ON was distinctly more effective than that of TAM and MEG. A similar potentiation of the antitumor effect of TAM and ON was observed in the NMU-tumor model. In DMBA-tumors, the concentration of progesterone receptors was found to increase after treatment for three days with TAM and ON. In hosts bearing DMBA-tumors, treatment with the combination of TAM and ON caused a reduction in ovarian and uterine weights. In the same animals, the basal level of progesterone was decreased in spite of a slight increase in the LH level. These findings suggest that the high antitumor effect of the combination of TAM and ON compared to the corresponding monotherapies can be related not only to the interaction of antihormones and receptors, but also to the up-regulation of PR and to a decrease in progesterone production. These data clearly suggest the sense of a combination of TAM with an antiprogestin in breast cancer treatment.

Antiovulatory effect of a single injection of pure antiestrogen ZK 191703 at early stage of rat estrus cycle.

The effects of ZK 191703 (ZK), a pure antiestrogen, on ovulation, follicle development and peripheral hormone levels were investigated in rats with 4-day estrus cycle and gonadotropin-primed immature rats in comparison to tamoxifen (TAM)-treatment. In adult rats, a single s.c. injection of ZK (5 mg/kg) or TAM (5 mg/kg) at an early stage of the estrus cycle (diestrus 9:00) inhibited ovulation, and was associated with suppression of the surge of preovulatory LH, FSH and progesterone. In rats treated with ZK or TAM at a late stage of the estrus cycle (proestrus 9:00), no inhibitory effects on ovulation, the gonadotropin and progesterone surge were detected. ZK treatment at diestrus 9:00, in contrast to TAM, increased the baseline LH level. When immature rats were treated with antiestrogens in the earlier stage of follicular development, 6 and 30 h but not 48 h or later after injection of gonadotropin (PMSG), ovulation was attenuated, associated with a lowered progesterone level. Unruptured preovulatory follicles were found in most of the ovaries from anovulatory animals treated with ZK or TAM. Antiestrogens, ZK and TAM administered at an early phase of the estrus cycle delay the follicular development functionally and inhibit ovulation in rats and suppression of the preovulatory progesterone surge.