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

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 IC (50) value of 59 n M and K(i) of 22 n M. L-39 also showed potent and competitive inhibition of 5α-reductase in human prostatic microsomes with IC (50) and K(i) values of 33 and 28 n M 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 n M) from binding to the androgen receptors. Androgen-ependent human próstate 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. © 2000 Cancer Research Campaign