title: Anti-tumour effects and pharmacokinetic profile of 17-(5'-isoxazolyl)androsta-4,16-dien-3-one (L-39) in mice: an inhibitor of androgen synthesis.
abstract: 17-(5'-Isoxazolyl)androsta-4,16-dien-3-one (L-39), a novel androstene derivative, was synthesized and evaluated in vitro and in vivo. L-39 showed potent and non-competitive inhibition of human testicular microsomal 17alpha-hydroxylase/C(17,20)-lyase with an IC50 value of 59 nM and Ki of 22 nM. L-39 also showed potent and competitive inhibition of 5alpha-reductase in human prostatic microsomes with IC50 and Ki values of 33 and 28 nM respectively. L-39 (5 microM) has also been shown to manifest anti-androgenic activity in cultures of human prostate cancer cell lines (LNCaP) by preventing the labelled synthetic androgen R1881 (5 nM) from binding to the androgen receptors. Androgen-dependent human prostate cancer xenografts (PC-82) were grown in nude mice and the effects of L-39 (50 mg kg(-1) day(-1)) on tumour growth and prostate-specific antigen (PSA) levels were determined after 28 days. L-39 significantly (P < 0.01) diminished tumour growth and wet weights to a similar extent as castration or flutamide treatment. L-39 also significantly (P < 0.01) reduced serum PSA levels by more than 80% in the mice bearing human prostate cancer xenografts. Pharmacokinetic studies were also conducted in male Balb/c mice. After subcutaneous administration of a single bolus dose, L-39 was rapidly absorbed into the systemic circulation. Peak plasma levels occurred at 0.75 h and then declined with a t(1/2) of 1.51 h. The bioavailability of L-39 after subcutaneous administration was 28.5%. These results demonstrate that L-39 is a potent inhibitor of androgen synthesis and is effective in reducing the growth of human prostate cancer xenografts in nude mice. Although improvements in the bioavailability are necessary, L-39 is a potential lead compound with this profile as an inhibitor of prostate cancer growth.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201, USA.
authors.forename: I P
authors.initials: IP
authors.lastname: Nnane
authors.forename: B J
authors.initials: BJ
authors.lastname: Long
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Ling
authors.forename: D N
authors.initials: DN
authors.lastname: Grigoryev
authors.forename: A M
authors.initials: AM
authors.lastname: Brodie
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000728:Androgens / Q000096:biosynthesis*; D000730:Androstadienes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes / Q000201:enzymology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009368:Neoplasm Transplantation; D011467:Prostate / Q000201:enzymology; D011470:Prostatic Hyperplasia / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013737:Testis / Q000201:enzymology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: C410803:17-(5'-isoxazolyl)androsta-4,16-dien-3-one; D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D000728:Androgens; D000730:Androstadienes; D018931:Antineoplastic Agents, Hormonal; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D013254:Steroid 17-alpha-Hydroxylase