Effect of combined treatment with the pure antiestrogen EM-800 and radiotherapy on the growth of human ZR-75-1 breast cancer xenografts in nude mice

Human breast tumors are usually composed of heterogeneous cell populations that exhibit different sensitivities to therapeutic agents. We therefore in vestigated the effect of treatment with various regimens of the novel pure antiestrogen EM-800, alone or in combination with external beam radiation t herapy, on the growth of human ZR-75-1 xenografts in athymic mice. The anim als received a maximal dose of EM-800 (300 pg, p.o.) and/or radiotherapy at the dose of 10 Gy, 2.5 Gy fractions were administered over a 9-day period in four sessions of 13.7 min each (250-kilovolt Siemens with 2 mm aluminum filtration at 90 cm from the source origin). EM-800 was administered p.o. o nce daily, whereas radiotherapy nas repeated every 35 days. Tumor size was expressed as a percentage of the initial tumor size, which was assigned a v alue of 100%, Average tumor size increased by 514% in ovariectomized mice s upplemented with estrone alone for 259 days compared with the pretreatment value. Treatment with radiotherapy or EM-800 alone resulted in 11 and 73% d ecreases in mean tumor size, respectively, whereas combined treatment given simultaneously at the beginning caused a dramatic 98% decrease in tumor si ze. The start of radiotherapy on day 35 in EM-800-treated mice, or converse ly, the start of EM-800 in irradiated mice at the 35-day time interval, res ulted in somewhat lower, 88% and 95%, decreases in tumor size, respectively . In animals receiving EM-800 alone, 40% of tumors disappeared, thus indica ting a cytotoxic effect caused by the estrogen blockade achieved with the p ure antiestrogen, Eighty-six % of the original tumors disappeared under con tinuous combined treatment. Most importantly, no tumor reappeared under est rogenic stimulation after stopping treatment, thus indicating cure of 86% o f the tumors in the group of animals who received the combination therapy. The present data indicate that combined treatment with EM-800 and radiother apy yields a faster response, a greater decrease in tumor size, and a highe r percentage of complete responses or tumor disappearance (cure) than eithe r treatment used alone. The present data also suggest that maximal benefits are achieved when the pure antiestrogen is administered continuously, star ting at the same tine as radiation therapy and continued without interrupti on as adjuvant therapy. The present data also clearly show that efficient b lockade of estrogens with a potent and pure antiestrogen is not only cytost atic but is cytotoxic and can lead to the disappearance of an important pro portion of tumors or cure.