• anti-androgen;
  • prostate cancer;
  • xenograft model

Objectives: The current study was undertaken to explore novel anti-androgens. We investigated a series of tetrahydroquinoline compounds and identified 1-(8-nitro-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl)ethane-1,2-diol (S-40542).

Methods: Affinity for androgen receptor of S-40542 was evaluated in receptor binding assay. Effects of repeated treatment with S-40542 and bicalutamide on prostate weight were examined in mice subcutaneously treated for 14days. Efficacy of S-40542 and bicalutamide against prostate cancer was evaluated in an androgen-dependent prostate cancer xenograft model using KUCaP-2 cell line. Plasma concentrations of these agents in mice after oral and subcutaneous administration were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) system.

Results: S-40542 displayed twofold higher affinity to androgen receptor than bicalutamide in vitro. Subcutaneous repeated administration of S-40542 (10–100 mg/kg) significantly reduced the prostate weight. Oral repeated treatment with S-40542 (30, 100 mg/kg) for 28 days significantly suppressed growth of KUCaP-2 tumor. Similar administration of bicalutamide also exerted significantly anti-tumor effect in the model. The serum prostate-specific antigen level was little influenced by the S-40542 treatment, while significantly decreased by bicalutamide. Oral treatment with S-40542 resulted in a dose-dependent elevation of the plasma concentration, and its Cmax and AUC were much lower than those of bicalutamide. The pharmacokinetic study showed that this agent had relatively short plasma half-life and low oral bioavailability.

Conclusion: S-40542 as well as bicalutamide has shown as an anti-androgen by reducing the prostate weight of mice. Repeated oral treatment with S-40542 was shown to significantly suppress tumor growth in the KUCaP-2 xenograft model.