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British Journal of Cancer (2001) 85(12), 19371943 2001 Cancer Research Campaigndoi: 10.1054/ bjoc.2001.2175, available online at http://www.idealibrary.com on http://www.bjcancer.comNuclear thymidylate synthase expression, p53
expression and 5FU response in colorectal carcinoma NACS Wong1, L Brett1, M Stewart2, A Leitch3, DB Longley4, MG Dunlop3, PG Johnston4, AM Lessells1 and DI Jodrell21Department of Pathology, University of Edinburgh Medical School, Teviot Place, Edinburgh EH8 9AG; 2ICRF Medical Oncology Unit, Department of Oncology,University of Edinburgh, and 3MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU; 4Department of Oncology, The Queens University ofBelfast, Belfast City Hospital Tower, Belfast BT9 7AB Summary 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 inmalignancy are unknown. 52 cases of primary colorectal carcinoma (CRC) and 24 cases of matched metastatic carcinoma were studiedimmunohistochemically using the monoclonal antibody TS106. The degree of nuclear TS immunostaining correlated closely with levels of TSmRNA expression amongst 10 CRCs studied. Strong nuclear immunostaining was seen in normal basal crypt colonocytes and germinalcentre cells, and in a varying proportion of adenocarcinoma cells. Amongst the primary carcinomas, higher TS nuclear expressionwas associated with prominent extracellular mucin production and right-sided location. Higher TS nuclear expression also showeda significant association with poorer response to protracted venous infusional 5FU therapy. There was no clear association between TSnuclear expression and Ki67 or p53 expression assessed immunohistochemically. There was a strong positive correlation betweenTS 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 mayrelate to the behaviour of CRCs. 2001 Cancer Research Campaign http://www.bjcancer.comKeywords: thymidylate synthase; colorectal carcinoma; immunohistochemistry; 5-fluorouracil; p53 protein; metastases Thymidylate synthase (TS) is the rate-limiting enzyme in the
production of thymine nucleotides, methylating deoxyuridine
monophosphate (dUMP) to form deoxythymidine monophosphate
(Peters et al, 1995). Inhibition of the enzyme is one of the main
modes of action of the chemotherapeutic agent, 5-fluorouracil
(5FU) (Thomas and Zalcberg, 1998). The drug is metabolised to
form fluorodeoxyuridine monophosphate (FdUMP) which binds
to TS, in competition with...