em-800 and Body-Weight

We demonstrated previously that continuous administration of EM-800, a SERM having pure antiestrogenic activity in the mammary gland and endometrium in combination with monthly radiotherapy caused a greater inhibition of human ZR 75 1 tumor growth in nude mice than either therapy used alone. To further optimize therapy, we have now examined the effect of various treatment sequences to determine the optimal treatment regimen in the same model. EM 800 was given at the maximally effective oral dose of 300 microg daily. External beam radiation therapy (RTX) was carried out (2 Gy/tumor/day, 5 days per week for 3 weeks) for a total of 30 Gy/tumor delivered directly to the tumor while shielding the rest of the animal body. There was no evidence of RTX-related morbidity. Continuous treatment with EM 800 was initiated either 3 weeks before or at the same time as RTX, immediately after RTX, or 3 weeks before and immediately after RTX. After 156 days of treatment, EM 800 alone caused a 75% decrease in average tumor area, an effect equivalent to that achieved by ovariectomy. RTX alone, on the other hand, caused a transient 30% decrease in tumor area regardless of treatment sequence, whereas combined treatment with EM 800 and RTX was superior to either treatment alone. Combined treatment with EM 800 and RTX both started on Day 1 caused the greatest (88%), most rapid (50% in 2 weeks) and sustained decrease in tumor size. The present data indicate that optimal reduction in breast tumor size is achieved by continuous administration of EM 800 and RTX started simultaneously on Day 1.

Topics: Animals; Benzopyrans; Body Weight; Combined Modality Therapy; Disease Progression; Disease-Free Survival; Estrogen Antagonists; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Propionates; Radiotherapy; Time Factors; Transplantation, Heterologous; Tumor Cells, Cultured

Human breast cancer proliferates as heterogeneous cell populations that exhibit different sensitivities to therapeutic agents. A logical approach to control these different cancer cell populations is the use of combined treatment with agents that block cell proliferation or induce apoptosis via different mechanisms. We therefore investigated the effect of treatment with the 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-recognized model of human breast cancer. Mice bearing estrone-releasing silastic implants as estrogenic stimulus received EM-800 or cyclophosphamide alone or in combination for 227 days. Cyclophosphamide (256 mg/kg/2 weeks) was administered by i.p. injection in 64 mg/kg fractions over 4 consecutive days with repetition of the cycle every 14 days. EM-800 was administered p.o. once daily at the maximally effective dose of 300 microg/mouse. After 227 days of treatment, average tumor size in mice receiving estrone alone was 192% higher than pretreatment. The average tumor size of mice treated with chemotherapy was reduced by 47%, whereas on the other hand, EM-800 caused a 81% decrease 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 addition of cyclophosphamide to the antiestrogen further decreased tumor size to as low as 15% of the pretreatment value. The combination of EM-800 and cyclophosphamide resulted in 95% of complete or partial responses compared with 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 progressed with EM-800 alone or in combination with cyclophosphamide. The present data show, for 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 classes of compounds having different mechanisms of action, could further improve breast cancer therapy above the results achieved with a potent and pure antiestrogen alone i

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzopyrans; Body Weight; Cyclophosphamide; Estrogen Antagonists; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Neoplasm Transplantation; Organ Size; Propionates; Transplantation, Heterologous; Uterus

The effect of EM-800, a new non-steroidal antiestrogen having pure antiestrogenic activity, was studied on chemical carcinogenesis induced by dimethylbenz(a)anthracene (DMBA) as well as on serum lipids and bone mass in the rat. Treatment with EM-800 orally, once daily, for 282 days (9 months), starting 3 days before DMBA administration, decreased the incidence of tumors from 95% in control animals to 60% (p < 0.01), 38% (p < 0.01), and 28% (p < 0.01) at the daily doses of 25 microg, 75 microg, and 250 microg, respectively. The average number of tumors per animal decreased from 4.5 +/- 0.5 tumors in the control group to 0.9 +/- 0.2 (p < 0.01), 0.5 +/-0.2 (p < 0.01), and 0.3 +/- 0.1 (p < 0.01) tumors in the rats treated with the above-indicated doses of the anti-estrogen. In addition, treatment with the increasing doses of EM-800 reduced serum cholesterol levels to 64%, 56%, and 48% of control, while serum triglycerides decreased to 31%, 28%, and 30% of control. Bone mineral content (BMC) and bone mineral density (BMD) of total skeleton, femur, and lumbar spine were not significantly affected following 282 days of treatment with EM-800. However, treatment with EM-800 inhibited the urinary ratio of hydroxyproline to creatinine (HP/Cr) from 14.0 +/- 3.90 micromol/mmol in controls to 7.6 +/-0.8 (p < 0.05), 6.8 +/- 0.8 (p < 0.01), and 6.8 +/- 1.1 (p < 0.01) micromol/mmol, respectively, while the same treatment had no effect on serum total alkaline phosphatase (tALP) activity or urinary calcium and phosphorus excretion. The 25 microg, 75 microg, and 250 microg daily doses of EM-800 inhibited uterine weight by 35% (p < 0.01), 62% (p < 0.01), and 66% (p < 0.01), while vaginal weight was reduced by 8% (p < 0.05), 30% (p < 0.01), and 38% (p < 0.01), respectively. In agreement with the 27% increment (p < 0.05) in ovarian weight at the highest anti-estrogen dose used, serum androstenedione (p < 0.05), androst-5-ene-3beta,17beta-diol (p < 0.01), testosterone (p < 0.05), and estradiol (p < 0.01) levels were increased. The present data show that EM-800 prevents the development of DMBA-induced mammary tumors while simultaneously inhibiting uterine and vaginal weight, reducing serum cholesterol and triglyceride levels, and having no adverse effect on bone mass following 9 months of treatment in the rat.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benzopyrans; Body Weight; Bone and Bones; Bone Density; Estrogen Antagonists; Female; Lipids; Mammary Neoplasms, Experimental; Organ Size; Ovary; Prodrugs; Propionates; Rats; Rats, Sprague-Dawley; Stereoisomerism; Uterus; Vagina