ENHANCEMENT OF THE ANTITUMOR EFFICACY OF THE ANTIPROGESTIN, ONAPRISTONE, BY COMBINATION WITH THE ANTIESTROGEN, ICI-164384

So far,no combination of endocrine treatments has been routinely used in the therapy of breast Cancer. It was, therefore, our interest to de termine whether the combination of the antiprogestin, onapristone (ON) , and the pure antiestrogen, ICI 164384 (ICI), might provide a more ef fective therapy than either monotherapy in experimental mammary tumors containing both estrogen and progesterone receptors. In the MXT-mamma ry tumor of the mouse, ON (5 mg/kg) administered for 3 weeks exerted a n ovariectomy-like antitumor effect (56% inhibition), whereas ICI (30 mg/kg) was weakly effective (28% inhibition). The combination of ON an d ICI was, however, distinctly more effective than the monotherapies o r ovariectomy, causing 78% inhibition. A similar potentation of antitu mor effect by the combination was manifested in the dimethylbenzanthra cene-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 ra tes of tumors found after treatment with ICI, ON, the combination and ovariectomy (complete and partial remission) were 15%, 46%, 71% and 10 0% 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 perip heral levels of estradiol and progesterone. ON had no appreciable effe ct on the uterine and ovarian weights. ICI reduced the uterine weight and the serum progesterone level. In the combination with ON, ICI reve rsed the effect of ON on the progesterone level without influencing th e luteinizing harmone and prolactin levels. These findings suggest tha t the augmentation of antitumor effectiveness by the combination of tw o antihormones can be ascribed not only to their effects at estrogen- and progesterone-receptor-binding sites, but also to the decrease in t he peripheral level of progesterone. Thus, an appropriate combination of antiprogestin and pure antiestrogen may be useful in the management of breast cancer.