Nuclear thymidylate synthase expression, p53 expression and 5FU response in colorectal carcinoma

N. A.C.S. Wong*, L. Brett, M. Stewart, A. Leitch, D. B. Longley, M. G. Dunlop, P. G. Johnston, A. M. Lessells, D. I. Jodrell

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)

Abstract

Thymidylate synthase (TS) is a key enzyme in DNA synthesis and is inhibited by metabolites of the chemotherapeutic agent 5-fluorouracil (5FU). Nuclear expression of TS in human tissue in vivo has not been characterised and its clinicopathological correlates in malignancy are unknown. 52 cases of primary colorectal carcinoma (CRC) and 24 cases of matched metastatic carcinoma were studied immunohistochemically using the monoclonal antibody TS106. The degree of nuclear TS immunostaining correlated closely with levels of TS mRNA expression amongst 10 CRCs studied. Strong nuclear immunostaining was seen in normal basal crypt colonocytes and germinal centre cells, and in a varying proportion of adenocarcinoma cells. Amongst the primary carcinomas, higher TS nuclear expression was associated with prominent extracellular mucin production and right-sided location. Higher TS nuclear expression also showed a significant association with poorer response to protracted venous infusional 5FU therapy. There was no clear association between TS nuclear expression and Ki67 or p53 expression assessed immunohistochemically. There was a strong positive correlation between TS nuclear expression in primary and metastatic CRC but the latter generally showed higher expression than matched primary tumour tissue. These findings confirm the nuclear expression of TS protein in human cells in vivo and provide new insight into how such expression may relate to the behaviour of CRCs.

Original languageEnglish
Pages (from-to)1937-1943
Number of pages7
JournalBritish Journal of Cancer
Volume85
Issue number12
DOIs
Publication statusPublished - 01 Jan 2001

Keywords

  • 5-fluorouracil
  • Colorectal carcinoma
  • Immunohistochemistry
  • Metastases
  • p53 protein
  • Thymidylate synthase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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