THE DIFFERENTIATING AGENT PHENYLACETATE INCREASES PROSTATE-SPECIFIC ANTIGEN PRODUCTION BY PROSTATE-CANCER CELLS

The prostatic-specific antigen (PSA) is the tumor marker most widely r elied upon for the monitoring of patients with prostate cancer. Recent ly, declines in the serum concentrations of PSA have been advocated as a surrogate marker of tumor response in clinical trials of investigat ional antitumor agents. We examined the hypothesis that this postulate may not apply to the evaluation of drugs such as phenylacetate, a dif ferentiating agent endowed with mechanisms of action different from th ose of classic cytotoxic chemotherapy. Using human prostatic carcinoma LNCaP cells as a model, we show that phenylacetate induces PSA produc tion despite inhibition of tumor cell proliferation. Incubation of LNC aP cultures with cytostatic doses of phenylacetate (3-10 mM) resulted in a three- to fourfold increase in PSA secretion per cell. This appea rs to result from upregulation of PSA gene expression, as indicated by elevated PSA mRNA steady-state levels in treated cells. The increase in PSA production per cell was confirmed in rats bearing subcutaneous LNCaP tumor implants that were treated systemically with phenylacetate . Further comparative studies indicate that upregulation of PSA is com mon to various differentiation inducers, including all-trans-retinoic acid, 1,25-dihydroxyvitamin D-3, and butyrate but is not induced by ot her antitumor agents of clinical interest such as suramin. We conclude that declines in PSA may be treatment specific and that the exclusive use of this criterion as a marker of disease response may mislead the proper evaluation of differentiating agents in prostate cancer patien ts. (C) 1996 Wiley-Liss, Inc.