Comparative Effects of Estrogen and Antiestrogens on Enzyme Activities in R3230AC Rat Mammary Tumors and Uteri of Tumor-bearing Animals

Growth of the R3230AC mammary tumor, an ovarian-autonomous but estrogen-responsive tumor in Fischer 344 rats, is markedly depressed by administration of antiestrogen or high doses of estradiol. We have examined the effects of antiestrogens and estradiol on the activity of several enzymes known to be modulated by estrogen, namely, glucose-6-phosphate dehydrogenase (G6PD), NADP-dependent malic dehydrogenase (malic enzyme), α-glycerol phosphate dehydrogenase, and peroxidase. In addition, we have compared the effects of antiestrogens and estradiol on these enzymatic activities in mammary tumors and uteri of R3230AC tumor-bearing animals to enable a comparison of hormonal and antihormonal action in these two estrogen-sensitive tissues. Rats were treated with antiestrogen or estradiol for 24 days beginning on the day of tumor transplantation. In mammary tumors, estradiol (25 µg s.c. in 0.15 m NaCI per day per rat) increased the activity of G6PD and malic enzyme 2-fold (expressed on a tissue weight or mg protein basis) and decreased the activity of α-glycerol phosphate dehydrogenase 2-fold; ovariectomy and antiestrogen treatments (250 µg s.c. in 0.15 m NaCI per day of 1-{2-[p-(3,4-dihydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]ethyl} pyrrolidine hydrochloride (U11,100A) or of two related antiestrogens, cis{3-[p-(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]-1,2-propanediol} (U23,469) and α-(4-pyrrolidinoethoxy)phenyl-4-methoxy-α^‘-nitrostilbene (CI-628) did not alter the activity from that of the diestrus control, and administration of antiestrogen along with estradiol blocked estradiol stimulation nearly completely. Tumor peroxidase activity was stimulated 5-fold by estradiol (25 µg) and 3-fold by antiestrogen (250 µg 1-{2-[p-(3,4-dihydro-6-methoxy-2-phenyl-1 -naphthyl)phenoxy]ethyl} pyrrolidine hydrochloride) above the levels in tumors of mature cycling animals. With concomitant administration of antiestrogen and estradiol, stimulation of peroxidase was reduced to the level seen with antiestrogen alone. In uteri of mammary tumor-bearing rats, some differences were seen. While estradiol significantly increased uterine weight and the activity of uterine G6PD (expressed on a tissue weight or mg protein basis), the activities of malic enzyme and peroxidase were not increased by estradiol above the levels seen in uteri of cycling animals. Ovariectomy and antiestrogen treatments, which markedly reduced uterine weight, suppressed the activities.