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

Abstract

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 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.

Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer: in vitro evidence and a phase I dose-escalating clinical trial

“…HT-29 SN-38R and HT-29 FUR cells required concentrations of SN-38 or FU about 10 times higher than wild-type HT-29 cells to exhibit similar rates of cytotoxicity or apoptosis (data not shown). Moreover, HT-29 FUR cells exhibited increased protein levels of TS (Figure1D, inset), the molecular target of FU (van Triest et al, 1999), which is in agreement with the well known observation that the upregulation of TS is responsible for resistance to FU (Wong et al, 2001). The cytotoxicity of the sequence of SN-38 followed by FU for 96 h was evaluated in HT-29, HT-29 SN-38R and HT-29 FUR cells.…”

“…This hypothetical mechanism of action provides a molecular rationale to our results showing that the synergistic activity of the SN-38 and FU sequence is partially conserved in colon carcinoma cells resistant to FU and characterised by increased levels of TS. It is also in agreement with the clinical observation that the FU-and IRI-based combination therapy is effective in patients pretreated with FU (Andre et al, 1999) and whose tumours are generally characterised by increased levels of TS (Wong et al, 2001) as well as with our results obtained in three patients previously treated with FU-based adjuvant chemotherapy who achieved partial response with this modified FU/IRI regimen. Furthermore, our results suggest that IRI-resistant CRC cells may be more sensitive to schedules with c.i.…”

Neuro-regulation of lower esophageal sphincter Predictive value of Ki67 and p53 in locally advanced rectal cancer: Correlation with thymidylate synthase and histopathological tumor regression after neoadjuvant 5-FU-based chemoradiotherapy

“…Kamoshida et al demonstrated in gastric cancer neoadjuvantly treated with S-1/cisplatin chemotherapy that high expression of TS and/or p53 in the pre-treatment biopsies predicted chemoresistance [40] . Other investig ators [41] were not able to find any cor relation between p53 and either TS or tumor regression. Our data do not suggest a predictive value of p53 immunohistochemistry in the neoadjuvant therapy of rectal cancer, either.…”

Role of biological markers in the clinical outcome of colon cancer

“…The situation in the adjuvant setting is less clear (Johnston et al, 1994;Findlay et al, 1997;Yamachika et al, 1998;Sanguedolce et al, 1998; Biological markers in colon cancer outcome O Nanni et al impact of TS on the natural history of colorectal cancer, the few studies conducted on mainly small series of patients not treated with systemic therapy (Yamachika et al, 1998;Sanguedolce et al, 1998;van Triest et al, 2000;Takenoue et al, 2000;Edler et al, 2000Edler et al, , 2002 have shown inconclusive results. In colorectal cancer patients treated with adjuvant 5-FUcontaining chemotherapy, both high (Johnston et al, 1994;Takenoue et al, 2000;Edler et al, 2002) and low (Cascinu et al, 2001;Wong et al, 2001) TS expression were found to be associated with a better clinical outcome. Our results and those of other studies (Findlay et al, 1997;Yamachika et al, 1998;Tomiak et al, 2001) did not highlight that TS was capable of predicting clinical outcome.…”