title: STX2171, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, is efficacious in vivo in a novel hormone-dependent prostate cancer model.
abstract: 17β-Hydroxysteroid dehydrogenases (17β-HSDs) catalyse the 17-position reduction/oxidation of steroids. 17β-HSD type 3 (17β-HSD3) catalyses the reduction of the weakly androgenic androstenedione (adione) to testosterone, suggesting that specific inhibitors of 17β-HSD3 may have a role in the treatment of hormone-dependent prostate cancer and benign prostate hyperplasia. STX2171 is a novel selective non-steroidal 17β-HSD3 inhibitor with an IC(50) of ∼200 nM in a whole-cell assay. It inhibits adione-stimulated proliferation of 17β-HSD3-expressing androgen receptor-positive LNCaP(HSD3) prostate cancer cells in vitro. An androgen-stimulated LNCaP(HSD3) xenograft proof-of-concept model was developed to study the efficacies of STX2171 and a more established 17β-HSD3 inhibitor, STX1383 (SCH-451659, Schering-Plough), in vivo. Castrated male MF-1 mice were inoculated s.c. with 1×10(7) cells 24 h after an initial daily dose of testosterone propionate (TP) or vehicle. After 4 weeks, tumours had not developed in vehicle-dosed mice, but were present in 50% of those mice given TP. One week after switching the stimulus to adione, mice were dosed additionally with the vehicle or inhibitor for a further 4 weeks. Both TP and adione efficiently stimulated tumour growth and increased plasma testosterone levels; however, in the presence of either 17β-HSD3 inhibitor, adione-dependent tumour growth was significantly inhibited and plasma testosterone levels reduced. Mouse body weights were unaffected. Both inhibitors also significantly lowered plasma testosterone levels in intact mice. In conclusion, STX2171 and STX1383 significantly lower plasma testosterone levels and inhibit androgen-dependent tumour growth in vivo, indicating that 17β-HSD3 inhibitors may have application in the treatment of hormone-dependent prostate cancer.
authors.affiliation: Oncology Drug Discovery and Women's Health Group, Division of Diabetes, Endocrinology and Metabolism, and Sterix Ltd., Imperial College London, UK.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Day
authors.forename: Paul A
authors.initials: PA
authors.lastname: Foster
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Tutill
authors.forename: Fabien
authors.initials: F
authors.lastname: Schmidlin
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sharland
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Hargrave
authors.forename: Nigel
authors.initials: N
authors.lastname: Vicker
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002369:Castration; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D011863:Radioimmunoassay; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000097:blood*; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C581976:1-acetyl-5-(2-(4-chlorophenoxy)phenylamino)-2,3,4,5-tetrahydrobenzo(b)azepine; D001552:Benzazepines; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D013739:Testosterone; D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3