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

Shingo Kamoshida, Hiroshi Matsuoka, Kazuya Shiogama, Atsuji Matsuyama, Ryoichi Shimomura, Ken Ichi Inada, Morito Maruta, Yutaka Tsutsumi

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Abstract

High expression of thymidylate synthase (TS) is allegedly associated with the chemoresistance to 5-fluorouracil (5-FU) in colorectal cancers. However, low TS expression does not necessarily imply chemosensitivity. Inactivation of p16INK4a correlates with poor prognosis in various cancers. We immunohistochemically evaluated the relationship between the expression of TS, p16INK4a, CDK4 and cyclin D1 and the effect of 5-FU-based chemotherapy in colorectal cancers. After antigen retrieval, immunoperoxidase staining was performed on the paraffin-embedded, biopsy and surgical specimens of 37 advanced colorectal cancers preoperatively treated with peroral administration of 5-FU derivatives. As a control group, 31 colorectal cancers without preoperative treatment were analysed. High TS expression was found in 23 (74%) of 31 tumors resected from histological non-responders and in 19 (61%) of 31 controls but in none of six responders. High p16INK4a expression was seen in 83% of the responders, 52% of the non-responders and 32% of the controls. The TS-low/p16INK4a-high phenotype was noted in 83% of the responders, but only in 3% of the non-responders (P = 0.0001). Induction of p16INK4a expression after chemotherapy was predominantly seen in the responders. Neither CDK4 nor cyclin D1 expression was related to the chemotherapeutic effects. In conclusion, the combination of low expression of TS and induction of p16INK4a after chemotherapy can be important indicators of the sensitivity to 5-FU-based chemotherapy in colorectal cancers.

Original languageEnglish
Pages (from-to)564-575
Number of pages12
JournalPathology International
Volume54
Issue number8
DOIs
Publication statusPublished - 01-08-2004

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Cyclin-Dependent Kinase 4
Thymidylate Synthase
Cyclin D1
Fluorouracil
Colorectal Neoplasms
Drug Therapy
Paraffin
Neoplasms
Staining and Labeling
Phenotype
Biopsy
Antigens
Control Groups

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

@article{471b883e98e747209d0107778ee22eed,
title = "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",
abstract = "High expression of thymidylate synthase (TS) is allegedly associated with the chemoresistance to 5-fluorouracil (5-FU) in colorectal cancers. However, low TS expression does not necessarily imply chemosensitivity. Inactivation of p16INK4a correlates with poor prognosis in various cancers. We immunohistochemically evaluated the relationship between the expression of TS, p16INK4a, CDK4 and cyclin D1 and the effect of 5-FU-based chemotherapy in colorectal cancers. After antigen retrieval, immunoperoxidase staining was performed on the paraffin-embedded, biopsy and surgical specimens of 37 advanced colorectal cancers preoperatively treated with peroral administration of 5-FU derivatives. As a control group, 31 colorectal cancers without preoperative treatment were analysed. High TS expression was found in 23 (74{\%}) of 31 tumors resected from histological non-responders and in 19 (61{\%}) of 31 controls but in none of six responders. High p16INK4a expression was seen in 83{\%} of the responders, 52{\%} of the non-responders and 32{\%} of the controls. The TS-low/p16INK4a-high phenotype was noted in 83{\%} of the responders, but only in 3{\%} of the non-responders (P = 0.0001). Induction of p16INK4a expression after chemotherapy was predominantly seen in the responders. Neither CDK4 nor cyclin D1 expression was related to the chemotherapeutic effects. In conclusion, the combination of low expression of TS and induction of p16INK4a after chemotherapy can be important indicators of the sensitivity to 5-FU-based chemotherapy in colorectal cancers.",
author = "Shingo Kamoshida and Hiroshi Matsuoka and Kazuya Shiogama and Atsuji Matsuyama and Ryoichi Shimomura and Inada, {Ken Ichi} and Morito Maruta and Yutaka Tsutsumi",
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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. / Kamoshida, Shingo; Matsuoka, Hiroshi; Shiogama, Kazuya; Matsuyama, Atsuji; Shimomura, Ryoichi; Inada, Ken Ichi; Maruta, Morito; Tsutsumi, Yutaka.

In: Pathology International, Vol. 54, No. 8, 01.08.2004, p. 564-575.

Research output: Contribution to journalArticle

TY - JOUR

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T2 - Significance of p16INK4a-mediated cellular arrest as an indicator of chemosensitivity to 5-fluorouracil

AU - Kamoshida, Shingo

AU - Matsuoka, Hiroshi

AU - Shiogama, Kazuya

AU - Matsuyama, Atsuji

AU - Shimomura, Ryoichi

AU - Inada, Ken Ichi

AU - Maruta, Morito

AU - Tsutsumi, Yutaka

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N2 - High expression of thymidylate synthase (TS) is allegedly associated with the chemoresistance to 5-fluorouracil (5-FU) in colorectal cancers. However, low TS expression does not necessarily imply chemosensitivity. Inactivation of p16INK4a correlates with poor prognosis in various cancers. We immunohistochemically evaluated the relationship between the expression of TS, p16INK4a, CDK4 and cyclin D1 and the effect of 5-FU-based chemotherapy in colorectal cancers. After antigen retrieval, immunoperoxidase staining was performed on the paraffin-embedded, biopsy and surgical specimens of 37 advanced colorectal cancers preoperatively treated with peroral administration of 5-FU derivatives. As a control group, 31 colorectal cancers without preoperative treatment were analysed. High TS expression was found in 23 (74%) of 31 tumors resected from histological non-responders and in 19 (61%) of 31 controls but in none of six responders. High p16INK4a expression was seen in 83% of the responders, 52% of the non-responders and 32% of the controls. The TS-low/p16INK4a-high phenotype was noted in 83% of the responders, but only in 3% of the non-responders (P = 0.0001). Induction of p16INK4a expression after chemotherapy was predominantly seen in the responders. Neither CDK4 nor cyclin D1 expression was related to the chemotherapeutic effects. In conclusion, the combination of low expression of TS and induction of p16INK4a after chemotherapy can be important indicators of the sensitivity to 5-FU-based chemotherapy in colorectal cancers.

AB - High expression of thymidylate synthase (TS) is allegedly associated with the chemoresistance to 5-fluorouracil (5-FU) in colorectal cancers. However, low TS expression does not necessarily imply chemosensitivity. Inactivation of p16INK4a correlates with poor prognosis in various cancers. We immunohistochemically evaluated the relationship between the expression of TS, p16INK4a, CDK4 and cyclin D1 and the effect of 5-FU-based chemotherapy in colorectal cancers. After antigen retrieval, immunoperoxidase staining was performed on the paraffin-embedded, biopsy and surgical specimens of 37 advanced colorectal cancers preoperatively treated with peroral administration of 5-FU derivatives. As a control group, 31 colorectal cancers without preoperative treatment were analysed. High TS expression was found in 23 (74%) of 31 tumors resected from histological non-responders and in 19 (61%) of 31 controls but in none of six responders. High p16INK4a expression was seen in 83% of the responders, 52% of the non-responders and 32% of the controls. The TS-low/p16INK4a-high phenotype was noted in 83% of the responders, but only in 3% of the non-responders (P = 0.0001). Induction of p16INK4a expression after chemotherapy was predominantly seen in the responders. Neither CDK4 nor cyclin D1 expression was related to the chemotherapeutic effects. In conclusion, the combination of low expression of TS and induction of p16INK4a after chemotherapy can be important indicators of the sensitivity to 5-FU-based chemotherapy in colorectal cancers.

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