Inhibitory effects of medroxyprogesterone acetate (MPA) and the pure antiestrogen EM-219 on estrone (E1)-stimulated growth of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat.
Estrogens are well known to play a predominant role in promoting the growth of DMBA-induced mammary tumors in the rat. Estrone (E1), a steroid having weak estrogenic activity, is one of most important estrogens in post-menopausal women, where it is converted into the potent estrogen estradiol (E2) by 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) in many peripheral tissues, including the mammary gland. In this report, we have studied the effect of a new antiestrogen (EM-219) (N-butyl, N-methyl-11-(3', 17'beta-dihydroxy-17'alpha-ethinyl-estra-1'3'5'(10'), 14'-tetraen-7'alpha-yl) undecanamide) on E1-stimulated growth of DMBA-induced mammary tumors and compared its effect with that of medroxyprogesterone acetate (MPA) alone or in combination. After 18 days, ovariectomy (OVX) reduced total tumor area to 29.6 +/- 7.1% of the original size, while E1 (1.0 microgram, twice daily) caused a 139 +/- 21% increase in tumor size in OVX animals. MPA (1.5 mg, twice daily) partially reversed the stimulatory effect of E1 to 66.0 +/- 9.0%, while the antiestrogen EM-219 (40 micrograms, twice daily) decreased tumor size to 70.0 +/- 10%. Combination of these two compounds led to a further inhibition of tumor size to 30.7 +/- 7.4% of the value found in OVX animals treated with E1. Tumor E2 levels decreased from 1688 +/- 155 pmoles/kg tissue in OVX animals receiving E1 to 709 +/- 92, 1347 +/- 98, and 184 +/- 11 pmoles/kg tissue in MPA-, EM-219-, and MPA+EM-219-treated OVX-E1 animals, respectively. Treatment of OVX animals with E1 increased by 69% the reductive activity of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) while MPA abolished completely this effect of E1. In the oxidative direction, treatment with E1, E1 + MPA, or E1 + EM-219 had minimal or no significant effect on the activity of 17 beta-HSD (vs OVX), while the combined treatment with MPA+EM-219 induced a 2-fold increase in 17 beta-HSD activity, thus leading to an increased conversion of E2 into E1. The present data show that combination of the pure antiestrogen EM-219 with MPA exerts a greater reduction in DMBA-induced mammary tumor growth and intratumoral E2 levels stimulated by E1 than either compound used alone. This interactive effect of the antiestrogen and MPA could at least partially be related to the increased inactivation of E2 into E1.(ABSTRACT TRUNCATED AT 400 WORDS)
Li
S
S
MRC Group in Molecular Endocrinology, CHUL Research Center, Québec, Canada.
Lévesque
C
C
Geng
C S
CS
Yan
X
X
Labrie
F
F
D015067:17-Hydroxysteroid Dehydrogenases / Q000187:drug effects / Q000378:metabolism; D015127:9,10-Dimethyl-1,2-benzanthracene / Q000037:antagonists & inhibitors*; D000311:Adrenal Glands / Q000033:anatomy & histology / Q000187:drug effects; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D004958:Estradiol / Q000097:blood / Q000378:metabolism; D004963:Estrenes / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004970:Estrone / Q000037:antagonists & inhibitors*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007986:Luteinizing Hormone / Q000097:blood; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D009376:Neoplasms, Hormone-Dependent / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects
C095268:EM 219; D004963:Estrenes; D004965:Estrogen Antagonists; D004970:Estrone; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D017258:Medroxyprogesterone Acetate; D015067:17-Hydroxysteroid Dehydrogenases