title: Nuclear thymidylate synthase expression, p53 expression and 5FU response in colorectal carcinoma.
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.
authors.affiliation: Department of Pathology, University of Edinburgh Medical School, Teviot Place, Edinburgh, EH8 9AG.
authors.forename: N A
authors.initials: NA
authors.lastname: Wong
authors.forename: L
authors.initials: L
authors.lastname: Brett
authors.forename: M
authors.initials: M
authors.lastname: Stewart
authors.forename: A
authors.initials: A
authors.lastname: Leitch
authors.forename: D B
authors.initials: DB
authors.lastname: Longley
authors.forename: M G
authors.initials: MG
authors.lastname: Dunlop
authors.forename: P G
authors.initials: PG
authors.lastname: Johnston
authors.forename: A M
authors.initials: AM
authors.lastname: Lessells
authors.forename: D I
authors.initials: DI
authors.lastname: Jodrell
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000201:enzymology*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020869:Gene Expression Profiling; D016158:Genes, p53; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D015203:Reproducibility of Results; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000096:biosynthesis* / Q000235:genetics; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D013940:Thymidylate Synthase; D005472:Fluorouracil