5-Fluorouracil selectively inhibits collagen synthesis

Neil W. Bulstrode, Vivek Mudera, D. Angus McGrouther, Adriaan O. Grobbelaar, Alison D. Cambrey

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Background: Fibroproliferative disorders, such as Dupuytren's contracture of the hand, are characterized by excessive production of collagen. 5-Fluorouracil has been used to treat fibroproliferative disorders of the eye and skin and is thought to inhibit thymidylate synthetase blocking DNA replication. 5-Fluorouracil has been shown to down-regulate fibroblast proliferation and differentiation in vitro. Methods: This study investigated the dose-dependent effect of 5-fluorouracil on fibroblast extracellular matrix production. Fibroblasts were derived from tendon and primary Dupuytren's disease of the hand, a fibroproliferative disorder of the palmar aponeurosis (n = 4 patients). Total collagen synthesis was determined by means of the incorporation of radiolabeled proline. Fibroblast secretion of the profibrotic factor transforming growth factor-β1 (TGF-β1) was measured by a sandwich enzyme-linked immunosorbent assay. Gene expression of collagen types I and III and TGF-β1 were quantified by means of reverse-transcriptase polymerase chain reaction assays. Results: The authors found that 5-fluorouracil caused a dose-dependent, selective, and specific decrease in collagen production by Dupuytren's fibroblasts compared with noncollagenous protein synthesis. By contrast, procollagen types I and III mRNA were unaffected by 5-fluorouracil treatment. These changes did not appear to be mediated by alterations in the endogenous secretion of TGF-β1 or its autocrine effect on collagen metabolism. Conclusions: The clinical implication is that 5-fluorouracil could possibly reduce extracellular matrix production and therefore reduce recurrence of Dupuytren's disease of the hand.
    Original languageEnglish
    Pages (from-to)209-221
    Number of pages12
    JournalPlastic and Reconstructive Surgery
    Volume116
    Issue number1
    DOIs
    Publication statusPublished - Jul 2005

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