Effects of the antiestrogen EM-800 (SCH 57050)and cyclophosphamide alone and in combination on growth of human ZR-75-1 breast cancer xenografts in nude mice

Human breast cancer proliferates as heterogeneous cell populations that exh ibit different sensitivities to therapeutic agents, A logical approach to c ontrol these different cancer cell populations is the use of combined treat ment with agents that block cell proliferation or induce apoptosis via diff erent mechanisms. We therefore investigated the effect of treatment with th e novel pure antiestrogen EM-800, alone or in combination with chemotherapy , on the growth of ZR-75-1 human breast tumors in nude mice, a well-recogni zed model of human breast cancer, Mice bearing estrone-releasing silastic i mplants as estrogenic stimulus received EM-800 or cyclophosphamide alone or in combination for 227 days. Cyclophosphamide (256 mg/kg/2 weeks) was admi nistered hy i.p. infection in 64 mg/kg fractions over 4 consecutive days wi th repetition of the cycle every 14 days. EM-800 was administered p.o. once daily at the maximally effective dose of 300 mu g/mouse. After 227 days of treatment, average tumor size in mice receiving estrone alone was 192%, hi gher than pretreatment, The average tumor size of mice treated with chemoth erapy was reduced by 47%, whereas on the other hand, EM-800 caused a 81% de crease of the value of the same parameter. The combined treatment (EM-800 cyclophosphamide), on the other hand, resulted in a 95% decrease in tumor size compared with control estrogen alone. In fact, EM-800 alone decreased tumor size to 55% of the value at the start of treatment, whereas the addit ion of cyclophosphamide to the antiestrogen further decreased tumor size to as low as 15% of the pretreatment value. The combination of EM-800 and cyc lophosphamide resulted in 95% of complete or partial responses compared wit h 61 and 27% with EM-800 and cyclophosphamide alone, respectively. In fact, in the combination therapy group, only one tumor remained stable, while 17 regressed >50% and four disappeared. It is noteworthy that no tumor progre ssed with EM-800 alone or in combination with cyclophosphamide, The present data show, fur the first time, that the addition of cyclophosphamide to a pure antiestrogen used at a maximal dose causes a more potent inhibition of human breast tumor growth, thus suggesting that combined treatment using a maximal dose of a pure antiestrogen and a chemotherapeutic agent(s), two c lasses of compounds having different mechanisms of action, could further im prove breast cancer therapy above the results achieved with a potent and pu re antiestrogen alone in estrogen-sensitive breast cancer.