So far, no combination of endocrine treatments has been routinely used in the
therapy of
breast Cancer. It was, therefore, our interest to determine whether the combination of the antiprogestin,
onapristone (ON), and the pure
antiestrogen,
ICI 164384 (ICI) might provide a more effective
therapy than either monotherapy in experimental mammary
tumors containing both
estrogen and
progesterone receptors. In the MXT-mammary
tumor of the mouse, ON (5 mg/kg) administered for 3 weeks exerted an
ovariectomy-like antitumor effect (56% inhibition), whereas ICI (30 mg/kg) was weakly effective (28% inhibition). The combination of ON and ICI was, however, distinctly more effective than the monotherapies or
ovariectomy, causing 78% inhibition. A similar potentiation of antitumor effect by the combination was manifested in the dimethylbenzanthracene-induced mammary
tumor of the rat when ON (5 mg/kg) and ICI (30 mg/kg) were administered once daily for 4 weeks (s.c.). The remission rates of
tumors found
after treatment with ICI, ON, the combination and
ovariectomy (complete and partial remission) were 15%, 46%, 71% and 100% respectively. In the animals bearing DMBA-induced
tumors, treatment with ON alone significantly increased the serum levels of
luteinizing hormone and
prolactin, but caused only a slight increase in the peripheral levels of
estradiol and
progesterone. ON had no appreciable effect on the uterine and ovarian weights. ICI reduced the uterine weight and the serum
progesterone level. In the combination with ON, ICI reversed the effect of ON on the
progesterone level without influencing the
luteinizing hormone and
prolactin levels. These findings suggest that the augmentation of antitumor effectiveness by the combination of two antihormones can be ascribed not only to their effects at
estrogen- and
progesterone-receptor-binding sites, but also to the decrease in the peripheral level of
progesterone. Thus, an appropriate combination of antiprogestin and pure
antiestrogen may be useful in the management of
breast cancer.