SELECTIVE GROWTH ARREST AND PHENOTYPIC REVERSION OF PROSTATE-CANCER CELLS-INVITRO BY NONTOXIC PHARMACOLOGICAL CONCENTRATIONS OF PHENYLACETATE

Differentiation therapy may provide an alternative for treatment of ca ncers that do not respond to cytotoxic chemotherapy or hormonal manipu lations. This hypothesis led us to evaluate the effect of a nontoxic d ifferentiation inducer, sodium phenylacetate (NaPA), on hormone-refrac tory prostate cancer, the second most common cause of cancer deaths in men. NaPA treatment of androgen-independent PC3 and DU145 prostate ce ll lines, like that of hormone-responsive LNCaP cultures, resulted in dose-dependent inhibition of cell proliferation. Similar treatments we re not significantly inhibitory to replicating normal endothelial cell s and skin fibroblasts. In addition to the selective cytostatic effect , NaPA induced reversion of the prostatic cells to a nonmalignant phen otype, evidenced by their reduced invasiveness and loss of tumorigenic ity in athymic mice. Phenotypic reversion was accompanied by alteratio ns in gene expression, including selective reduction in tumor growth f actor-beta2 mRNA levels and increased amounts of class I major histoco mpatibility complex HLA transcripts. Furthermore, there was a decrease in tumor-associated proteolysis mediated by urokinase plasminogen act ivator, a molecular marker of disease progression in humans. When tumo r cells were treated with NaPA together with suramin, a drug with demo nstrable activity in patients, there was complete abrogation of cell g rowth under conditions in which each treatment alone produced only a p artial effect. The in vitro antineoplastic activity was observed with drug concentrations that have been achieved in humans with no signific ant toxicities, suggesting that PA, used alone or in combination with other antitumor agents, warrants evaluation in the treatment of advanc ed prostatic cancer.