Phenylacetate is an inhibitor of prostatic growth and development in organ culture

Benign prostatic hyperplasia (BPH) is the most common proliferative disease affecting men, and the obstructive uropathy it causes results in serious morbidity and financial cost. Phenylacetate (PA) is a small molecule that is a product of phenylalanine metabolism and is normally present in the mammalian circulation at very low levels. It has long been safely used in humans to treat the hyperammonemia resulting from urea synthesis disorders and liver failure. It has recently been investigated as an anticancer agent because it decreased growth and increased differentiation of a variety of human neoplasms, including prostate cancer in which a phase I trial has recently been completed.

Because of PA's growth-inhibitory effects on a variety of cell lines and the idea that BPH is due to a reawakening of embryonic-like inductive activity in prostatic stromal cells, which then induce development of epithelial nodules, we examined the effect of PA on serum-free organ cultures of developing rat prostates.

We found that PA markedly decreased rat prostatic growth and ductal morphogenesis at concentrations that have previously been well tolerated in patients. In ventral prostates grown for 7 days in organ culture, histodifferentiation was inhibited as measured by a marked decrease in ductal lumen formation and ductal branching morphogenesis. This inhibition of differentiation was confirmed by using cytokeratin antibodies specific for basal and luminal cells. Synthesis of DNA was also significantly decreased per organ with PA. The growth inhibitory effects of PA were reversible, and the mechanism did not appear to be due to glutamine or glycine deprivation, or androgen receptor inhibition.

In common with earlier studies, we found that PA inhibits prostatic growth; however, in our organ culture system, differentiation was also largely inhibited. These studies indicate that there may be a role for PA in treating BPH or in elucidating the mechanism by which it occurs since BPH apparently involves the neoformation of ductal-acinar tissue in aged men via mechanisms fundamentally similar if not identical to those in fetal prostatic development.