PHENYLACETATE INHIBITS ISOPRENOID BIOSYNTHESIS AND SUPPRESSES GROWTH OF HUMAN PANCREATIC-CARCINOMA

Background. Phenylacetate is growth inhibitor for a variety of tumors at concentrations that have been safely achieved in human beings. This antitumor effect is related to inhibition of the isoprenoid synthetic pathway by blocking the enzyme, mevalonate pyrophosphate (MVAPP) deca rboxylase. The purpose of this study was to evaluate the effects of ph enylacetate on human pancreatic carcinoma. Methods. For in vitro studi es, six human pancreatic carcinoma cell lines (BxPc, AsPc, MIAPaCa-2, Panc-1, CFPAC, and HS 766T) were studied. For in vivo studies, nude mi ce were inoculated with pancreatic cells (BxPc and MIA PaCa-2) and ran domized to receive phenylacetate or saline control. Results. Phenylace tate produces reversible in vitro growth arrest at doses of 2.5 to 10 mmol. The antiproliferative effect is cytostatic, producing accumulati on of cells in G1, and is not associated with cell toxicity. Systemic treatment of nude mice bearing heterotopic human pancreatic carcinoma results in growth inhibition of tumors without host toxicity. Phenylac etate blocks the processing of mevalonate to isopentenyl-pyrophosphate by inhibiting MVAPP and exhibits suppression of biosynthetic pathways requiring isoprenoids, including cholesterol and dolichol biosynthesi s, protein glycosylation, and isoprenylation of proteins. Conclusions. These results indicate that phenylacetate has cytostatic activity in pancreatic carcinoma and support the conclusion that suppression of mu ltiple biosynthetic pathways requiring isoprenoids is contributing to the drug's antiproliferative action. The safety profile and efficacy o f phenylacetate make it an attractive agent for the treatment of pancr eatic cancer.