IMMUNOHISTOCHEMICAL DEMONSTRATION OF THYMIDYLATE SYNTHASE (TS), p53 PROTEIN AND BCL-XL PROTEIN IN COLORECTAL CANCER WITH PREOPERATIVE PERORAL CHEMOTHERAPY

Abstract

of apoptosis, p53 protein, selection of patients, thymidylate synthase (TS). AbstractHigh expression of thymidylate synthase (TS), p53 protein and bcl-XL protein has been suggested to be associated with chemoresistance of colorectal malignancies. The significance of TS, p53 protein and bcl-XL protein as predictive parameters of effects of 5-fluorouracil (5-FU)-based chemotherapy on colorectal cancers was evaluated.Immunoperoxidase staining of TS, p53 protein and bcl-XL protein was performed on formalin-fixed, paraffin-embedded, 1opsied and resected specimens from 37 patients with advanced colorectal cancers, preoperatively treated with 5-FU derivatives per os. When more than one third of the cancer cells were stained, the lesions were considered high for antigen expression. High TS expression in the resected tumors was seen in 23 (74%) of 31 histologic non-responders but none in six responders. TS expression in preoperative biopsies and resected specimens was concordant in 80% of cases when two or more biopsy specimens were available.The rate of high TS expression was comparable in the control non-treated group. There was no difference between chemotherapeutic effects and the expression of p53 protein or bcl-XL protein.

Immunohistochemical analysis of thymidylate synthase, p16INK4a, cyclin‐dependent kinase 4 and cyclin D1 in colorectal cancers receiving preoperative chemotherapy: Significance of p16INK4a‐mediated cellular arrest as an indicator of chemosensitivity to 5‐fluorouracil

“…In the present study, we immunohistochemically investigated the relationship between the chemotherapeutic effects of 5‐FU derivatives and the expression of p16 INK4a , CDK4, cyclin D1 and TS in biopsy specimens and resected tumors of advanced colorectal cancers preoperatively treated with peroral administration of 5‐FU derivatives. We have previously examined and reported the TS expression levels in relation to the chemotherapeutic effects 8 . We demonstrate here that 5‐FU‐induced high p16 INK4a expression in tumors of the low TS expression group can be a relevant and useful indicator in determining the chemosensitivity to 5‐FU.…”

“…It has been suggested that high expression of TS is associated with the 5‐FU resistance of colorectal cancer cells and the poor prognosis of colorectal cancer patients 3–7 . We recently assessed the immunohistochemical expression of TS and p53 protein in the same biopsy and the surgical samples of advanced colorectal cancers preoperatively treated with 5‐FU derivatives 8 . High TS expression in resected tumors was demonstrated in 74% of the histological non‐responders but none in the responders, whereas there was no association of the expression of p53 with the chemotherapeutic effects.…”

Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

“…However, the TS induction after drug exposure has not been documented in gastric cancer patients undergoing fluoropyrimidine-based chemotherapy (Uchida et al, 2001). A similar discrepancy between in vitro and in vivo systems has found in colorectal cancer (Peters et al, 2000;Uchida et al, 2001;Kamoshida et al, 2003b).…”

“…Thymidylate synthase (Yeh et al, 1998;Miyamoto et al, 2000). The reason for the difference is explained as follows: (1) to the best of our belief, TS staining method employed in our study is very sensitive, suitable and reproducible (Kamoshida et al, 2003a); (2) in our previous studies using colorectal cancer specimens, 30% was defined as a threshold level of TS expression (Kamoshida et al, 2003b(Kamoshida et al, , 2004. It has been reported that the mean TS mRNA level in gastric cancers is 1.6-to 1.7-fold higher than that in colorectal cancers, and the TS mRNA level is closely correlated with immunohistochemical expression of TS (Johnston et al, 1995;Uchida et al, 2001).…”

“…The evaluation of biopsy specimens was regarded appropriate when two or more biopsy pieces were available, as reported previously (Kamoshida et al, 2003b).…”