Evaluation of inhibitors for 17beta-hydroxysteroid dehydrogenase type 1 in vivo in immunodeficient mice inoculated with MCF-7 cells stably expressing the recombinant human enzyme.
17Beta-hydroxysteroid dehydrogenase (17HSD1) is an enzyme activating estrone (E1) to estradiol (E2). In the present study, a mechanistic animal model was set up for evaluating putative inhibitors for the human enzyme in vivo. Estrogen-dependent MCF-7 human breast carcinoma cells were stably transfected with a plasmid expressing human 17HSD1. These cells formed estrogen-dependent tumors in immunodeficient mice. In the optimized model, tumor sizes were decreased in both ovariectomized and intact vehicle-treated mice, whereas they were maintained or slightly increased in mice supplemented 2 weeks with an appropriate dose of the 17HSD1-substrate E1. Tumor sizes in mice treated with 0.1 micromol/kg/d of E1 were reduced by administering 5 micromol/kg/d of different 17HSD1-inhibitors and a 86% reduction in size was detected with the most potent inhibitor. A dose-response relationship in the inhibitory effect of this compound further confirmed the validity of the model for testing the drug candidates in vivo.
Husen
B
B
Solvay Pharmaceuticals Research Laboratories, PH-REL, Hans-Böckler-Allee 20, 30173 Hannover, Germany. bettina.husen@solvay.com
Huhtinen
K
K
Poutanen
M
M
Kangas
L
L
Messinger
J
J
Thole
H
H
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics; D004970:Estrone / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D004970:Estrone; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D004960:Estradiol Dehydrogenases