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Comparative Effects of Estrogen and Antiestrogens on Enzyme Activities in R3230AC Rat Mammary Tumors and Uteri of Tumor-bearing Animals¹

Department of Physiology and Biophysics, University of Illinois, and School of Basic Medical Sciences, University of Illinois College of Medicine, Urbana, Illinois 61801

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), -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 NaCl 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 -glycerol phosphate dehydrogenase 2-fold; ovariectomy and antiestrogen treatments (250 µg s.c. in 0.15 M NaCl 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 -(4-pyrrolidinoethoxy)phenyl-4-methoxy-'-nitrostilbene (Cl-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 of these three enzymes far below the control level. When estradiol was administered along with antiestrogen, uterine weights and malic enzyme activity remained depressed. Estradiol stimulation of G6PD was reduced by antiestrogen, and uterine peroxidase activity returned to the high control level in antiestrogen plus estradiol-treated animals.

Hence, although antiestrogens and estrogens both reduce growth of R3230AC mammary tumors, the results indicate that their effects on tumor enzyme activities differ. Also, although the growth of both tumor and uterus is depressed by antiestrogen administration to mature cycling rats, the effects of antiestrogens on the activity of the same enzyme in tumor and uterus are frequently different.

¹ Supported by NIH Grants USPHS CA 18119 from the National Cancer Institute and HD 06726 and HD 07028 from the National Institute of Child Health and Human Development. Reported, in part, at the 61st Annual Endocrine Society Meeting, June 1979 (19).

² To whom requests for reprints should be addressed at Department of Physiology and Biophysics, 524 Burrill Hall, University of Illinois, Urbana, Ill. 61801.

Received 2/19/80. Accepted 5/22/80.

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