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Dupuytren’s Disease of the hand. The potential for reducing fibrosis using 5-Fluorouracil.

Bulstrode, Neil; (2002) Dupuytren’s Disease of the hand. The potential for reducing fibrosis using 5-Fluorouracil. Doctoral thesis (M.D.), UCL (University College London). Green open access

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Abstract

Dupuytren's disease is a progressive fibroproliferative disorder leading to reduced hand function. The main treatment is surgical correction but post-operative recurrence is high. Dupuytren's is characterised by palmar and digital nodules and cords with increased myofibroblast proliferation and excessive extracellular matrix production. Review of the literature establishes that transforming growth factor β-1 (TGFβ-1) has been shown to increase myofibroblast differentiation, fibroblast proliferation and extracellular matrix production acting via an autocrine loop. 5-fluorouracil (5-fu) has been reported to reduce fibroblast proliferation and differentiation in vitro and to reduce adhesion formation in a tendon injury animal model. The hypothesis tested in this project was that 5-fu would reduce the profibrotic characteristics of fibroblasts in culture. 5-fu could therefore reduce the postoperative recurrence rates in Dupuytren's disease. The investigation would require the establishment of the following cell cultures, tendon and Dupuytren's from nine and 12 subjects respectively. Total collagen synthesis was investigated by measuring the incorporated radioisotope, tritiated proline, in collagenase digestible samples. It was found that total collagen synthesis was specifically and selectively reduced by 5-fu compared with non-collagenous protein synthesis when fibroblasts were incubated with or without exogenous TGFβ-1. Gene expression for collagen types I and III was measured by RT-PCR. Basal collagen type III expression was found to be increased compared with collagen type I expression for both control and Dupuytren's fibroblasts. Basal collagen type III expression was increased for Dupuytren's compared with control fibroblasts. Pre-treatment with 5-fu did not induce a reduction in gene expression for collagen types I and III compared with vehicle control treated cells. TGFβ-1 secretion was assessed by a sandwich ELISA. TGFβ-1 secretion was found to be increased by fibroblasts from Dupuytren's compared with controls. Pre-treatment with 5-fu did not induce a reduction in TGFβ-1 secretion. Gene expression for collagen and TGFβ-1 was measured by reverse transcription-polymerase chain reaction. Basal TGFβ-1 gene expression was found to be increased in Dupuytren's fibroblasts compared with controls. A double blind prospective randomised clinical trial investigating the effect of 5-fu in reducing post-operative recurrence rates in Dupuytren's disease has been established by the author. Experience to date has shown that 5-fu has not caused a delay in wound healing. 5-fu treatment did not adversely affect the early (up to six months) surgical outcome when compared with control treated digits. The clinical picture regarding recurrence rates will become clearer with increased length of follow-up and number of patients. The transition has therefore been made from in vitro investigation to commencing a prospective randomised controlled clinical trial.

Type: Thesis (Doctoral)
Qualification: M.D.
Title: Dupuytren’s Disease of the hand. The potential for reducing fibrosis using 5-Fluorouracil.
Event: University of London
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/120159
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