Agonistic effects of the anti-androgen bicalutamide in part limit a long-lasting response in CRPC patients. Carbidopa is a potent drug that inhibits coactivation function of the androgen-receptor (AR) coactivator protein, L-dopa decarboxylase. Carbidopa has previously been shown to retard prostate tumor growth and PSA production in xenograft experiments. These researchers hypothesized that pharmacological targeting of the AR-axis by combination treatment of bicalutamide plus carbidopa would enhance the antitumor activity in vitro and in vivo compared to single use of each drug. Carbidopa was tested for its ability to enhance the effects of bicalutamide in cell viability assays and PSA transactivation by luciferase assay in LNCaP and C4-2 cells. For in vivo xenograft studies, LNCaP cells were inoculated sub-cutaneously in athymic nude mice. Mice were castrated and after CRPC progression randomly assigned to treatments with carbidopa (50mg/kg) and bicalutamide (50mg/kg) as monotherapy or in combination. Tumor volume and serum PSA were evaluated weekly.
They found that combination treatment with carbidopa plus bicalutamide significantly inhibited cell growth for both LNCaP and C4-2 cells. In LNCaP cells, bicalutamide mono treatment inhibited cell growth by 48%, while the combination treatment reduced cell growth by 62% compared to control. Similarly in C4-2 cells, bicalutamide mono and combination treatments inhibited cell growth by 49% and 68%, respectively. The combination treatment also decreased androgen-induced PSA transactivation by 75% in LNCaP cells and by 65% in C4-2 cells compared to control, while bicalutamide mono therapy only reduced PSA levels by 27% (LNCaP) and 29% (C4-2). In vivo, bicalutamide monotherapy delayed the growth rate of LNCaP CRPC tumors by 3.2-fold, while combination treatment reduced tumor growth by 6.8-fold compared to control. Serum PSA production was also reduced 2.5-fold with bicalutamide mono-treatment, while the combination therapy reduced PSA progression by 4.3-fold compared to control.
Presented by Christian Thomas, et al. at the American Urological Association (AUA) Annual Meeting - May 14 - 19, 2011 - Walter E. Washington Convention Center, Washington, DC USA
Reported for UroToday by Christopher P. Evans, MD, FACS, Professor and Chairman, Department of Urology, University of California, Davis, School of Medicine.
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