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 17α-hydroxylase/C(17,20)-lyase with an IC50 value of 59 nM and K(i) of 22 nM. L-39 also showed potent and competitive inhibition of 5α-reductase in human prostatic microsomes with IC50 and K values of 33 and 28 nM respectively. L-39 (5 μM) 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. (C) 2000 Cancer Research Campaign.
|Original language||English (US)|
|Number of pages||9|
|Journal||British journal of cancer|
|State||Published - 2000|
- Prostate cancer
ASJC Scopus subject areas
- Cancer Research