Phenylacetate inhibits isoprenoid biosynthesis and suppresses growth of human pancreatic carcinoma

Lawrence Harrison, D. C. Wojciechowicz, M. F. Brennan, P. B. Paty

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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) decarboxylase. The purpose of this study was to evaluate the effects of phenylacetate on human pancreatic carcinoma. Methods. For in vitro studies, six human pancreatic carcinoma cell lines (BxPc, AsPc, MIAPaCa-2, Panc-1, CFPAC, and HS 766T) were studied. For in vivo studies, nude mice were inoculated with pancreatic cells (BxPc and MIA PaCa-2) and randomized to receive phenylacetate or saline control. Results. Phenylacetate produces reversible in vitro growth arrest at doses of 2.5 to 10 mmol. The antiproliferative effect is cytostatic, producing accumulation 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. Phenylacetate blocks the processing of mevalonate to isopentenyl- pyrophosphate by inhibiting MVAPP and exhibits suppression of biosynthetic pathways requiring isoprenoids, including cholesterol and dolichol biosynthesis, 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 multiple biosynthetic pathways requiring isoprenoids is contributing to the drug's antiproliferative action. The safety profile and efficacy of phenylacetate make it an attractive agent for the treatment of pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)541-550
Number of pages10
JournalSurgery
Volume124
Issue number3
DOIs
StatePublished - Jan 1 1998
Externally publishedYes

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Terpenes
Growth
Biosynthetic Pathways
pyrophosphomevalonate decarboxylase
Cytostatic Agents
Nude Mice
Protein Prenylation
Dolichol
Mevalonic Acid
Growth Inhibitors
Pancreatic Carcinoma
phenylacetic acid
Pancreatic Neoplasms
Glycosylation
Neoplasms
Cholesterol
Safety
Cell Line
Enzymes
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Surgery

Cite this

Harrison, Lawrence ; Wojciechowicz, D. C. ; Brennan, M. F. ; Paty, P. B. / Phenylacetate inhibits isoprenoid biosynthesis and suppresses growth of human pancreatic carcinoma. In: Surgery. 1998 ; Vol. 124, No. 3. pp. 541-550.
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Phenylacetate inhibits isoprenoid biosynthesis and suppresses growth of human pancreatic carcinoma. / Harrison, Lawrence; Wojciechowicz, D. C.; Brennan, M. F.; Paty, P. B.

In: Surgery, Vol. 124, No. 3, 01.01.1998, p. 541-550.

Research output: Contribution to journalArticle

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T1 - Phenylacetate inhibits isoprenoid biosynthesis and suppresses growth of human pancreatic carcinoma

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AU - Brennan, M. F.

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