Thymidylate synthetase (TS) genotype and TS/dihydropyrimidine dehydrogenase mRNA level as an indicator in determining chemosensitivity to 5-fluorouracil in advanced gastric carcinoma

Fumiki Toriumi, Tetsuro Kubota, Yoshiro Saikawa, Masashi Yoshida, Yoshihide Otani, Masahiko Watanabe, Koichiro Kumai, Masaki Kitajima

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Background: One of the target enzymes of 5-fluorouracil (5-FU) is thymidylate synthetase (TS). The DNA sequence of the TS gene includes either double or triple tandem 28-bp repeats within the promoter region, such that TS genotypes can be classified as homozygous 3R/3R, heterozygous 2R/3R or homozygous 2R/2R. Several recent studies have shown that TS genotype affects mRNA expression, with 3R/3R homozygotes showing higher TS mRNA expression compared to the other genotypes. Purpose: We analyzed the TS genotype TS and dihydropyrimidine dehydrogenase (DPD) mRNA expression levels in 22 advanced gastric carcinoma patients, and analyzed results with respect to patient 5-FU chemosensitivity, as detected by the tetrazolium-based colorimetric (MTT) assay and survival outcome. Patients and Methods: Between September 2001 and April 2002, 22 Japanese patients with advanced gastric carcinoma were evaluated. Informed written consent was obtained from all patients and the study was approved by the ethical committee at our University Hospital Fresh surgical specimens from carcinoma lesions were enzymatically dissociated and incubated with 5-FU at a concentration of 50 μg/ml for 48 hours to determine the inhibition rate as detected by MTT assay. Normal and tumor tissue and peripheral blood samples were collected and stored at -80 °C until assay for TS genotype and TS and DPD mRNA level. The TS genotype was assessed by PCR assay using peripheral monocytes, since monocyte genotypes represent the genotype of normal and tumor tissues. Quantification of TS and DPD mRNA levels was performed using real-time PCR Survival outcome was assessed according to the disease-free survival period in cases with similar clinical backgrounds. Results: TS genotyping revealed 19 3R/3R homozygotes and 32R/3R heterozygotes. After analysis of normal and tumor tissues, samples from homozygote 3R/3R cases showed higher TS mRNA expression than heterozygote 2R/3R cases, which was statistically significant at p<0.05. We also observed a statistically significant correlation in TS mRNA levels between normal and tumor tissues, while no significant correlation was observed for DPD mRNA levels between normal and tumor tissues. While no relationship between 5-FU chemosensitivity and TS genotype or mRNA expression was observed, cases with high DPD mRNA expression were resistant to 5-FU and exhibited poor survival outcomes. Conclusion: While TS genotype affected TS mRNA expression in both normal and tumor tissues in advanced gastric cancer, there is no relationship between TS genotype or mRNA expression level and 5-FU chemosensitivity. Conclusion: Our finding, that DPD mRNA expression appears to be a factor in determining 5-FU chemosensitivity and the survival outcome of advanced gastric cancer patients, is comparable with previous reports.

Original languageEnglish
Pages (from-to)2455-2463
Number of pages9
JournalAnticancer Research
Volume24
Issue number4
Publication statusPublished - 2004 Jul

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Dihydrouracil Dehydrogenase (NADP)
Thymidylate Synthase
Fluorouracil
Stomach
Genotype
Carcinoma
Messenger RNA
Homozygote
Neoplasms
Survival
Heterozygote
Stomach Neoplasms
Monocytes

Keywords

  • 5-Fluorouracil
  • Chemosensitivity
  • Dihydropyrimidine dehydrogenase
  • Gastric cancer
  • Tandem repeat
  • Thymidylate synthetase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Thymidylate synthetase (TS) genotype and TS/dihydropyrimidine dehydrogenase mRNA level as an indicator in determining chemosensitivity to 5-fluorouracil in advanced gastric carcinoma. / Toriumi, Fumiki; Kubota, Tetsuro; Saikawa, Yoshiro; Yoshida, Masashi; Otani, Yoshihide; Watanabe, Masahiko; Kumai, Koichiro; Kitajima, Masaki.

In: Anticancer Research, Vol. 24, No. 4, 07.2004, p. 2455-2463.

Research output: Contribution to journalArticle

Toriumi, F, Kubota, T, Saikawa, Y, Yoshida, M, Otani, Y, Watanabe, M, Kumai, K & Kitajima, M 2004, 'Thymidylate synthetase (TS) genotype and TS/dihydropyrimidine dehydrogenase mRNA level as an indicator in determining chemosensitivity to 5-fluorouracil in advanced gastric carcinoma', Anticancer Research, vol. 24, no. 4, pp. 2455-2463.
Toriumi, Fumiki ; Kubota, Tetsuro ; Saikawa, Yoshiro ; Yoshida, Masashi ; Otani, Yoshihide ; Watanabe, Masahiko ; Kumai, Koichiro ; Kitajima, Masaki. / Thymidylate synthetase (TS) genotype and TS/dihydropyrimidine dehydrogenase mRNA level as an indicator in determining chemosensitivity to 5-fluorouracil in advanced gastric carcinoma. In: Anticancer Research. 2004 ; Vol. 24, No. 4. pp. 2455-2463.
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abstract = "Background: One of the target enzymes of 5-fluorouracil (5-FU) is thymidylate synthetase (TS). The DNA sequence of the TS gene includes either double or triple tandem 28-bp repeats within the promoter region, such that TS genotypes can be classified as homozygous 3R/3R, heterozygous 2R/3R or homozygous 2R/2R. Several recent studies have shown that TS genotype affects mRNA expression, with 3R/3R homozygotes showing higher TS mRNA expression compared to the other genotypes. Purpose: We analyzed the TS genotype TS and dihydropyrimidine dehydrogenase (DPD) mRNA expression levels in 22 advanced gastric carcinoma patients, and analyzed results with respect to patient 5-FU chemosensitivity, as detected by the tetrazolium-based colorimetric (MTT) assay and survival outcome. Patients and Methods: Between September 2001 and April 2002, 22 Japanese patients with advanced gastric carcinoma were evaluated. Informed written consent was obtained from all patients and the study was approved by the ethical committee at our University Hospital Fresh surgical specimens from carcinoma lesions were enzymatically dissociated and incubated with 5-FU at a concentration of 50 μg/ml for 48 hours to determine the inhibition rate as detected by MTT assay. Normal and tumor tissue and peripheral blood samples were collected and stored at -80 °C until assay for TS genotype and TS and DPD mRNA level. The TS genotype was assessed by PCR assay using peripheral monocytes, since monocyte genotypes represent the genotype of normal and tumor tissues. Quantification of TS and DPD mRNA levels was performed using real-time PCR Survival outcome was assessed according to the disease-free survival period in cases with similar clinical backgrounds. Results: TS genotyping revealed 19 3R/3R homozygotes and 32R/3R heterozygotes. After analysis of normal and tumor tissues, samples from homozygote 3R/3R cases showed higher TS mRNA expression than heterozygote 2R/3R cases, which was statistically significant at p<0.05. We also observed a statistically significant correlation in TS mRNA levels between normal and tumor tissues, while no significant correlation was observed for DPD mRNA levels between normal and tumor tissues. While no relationship between 5-FU chemosensitivity and TS genotype or mRNA expression was observed, cases with high DPD mRNA expression were resistant to 5-FU and exhibited poor survival outcomes. Conclusion: While TS genotype affected TS mRNA expression in both normal and tumor tissues in advanced gastric cancer, there is no relationship between TS genotype or mRNA expression level and 5-FU chemosensitivity. Conclusion: Our finding, that DPD mRNA expression appears to be a factor in determining 5-FU chemosensitivity and the survival outcome of advanced gastric cancer patients, is comparable with previous reports.",
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AU - Toriumi, Fumiki

AU - Kubota, Tetsuro

AU - Saikawa, Yoshiro

AU - Yoshida, Masashi

AU - Otani, Yoshihide

AU - Watanabe, Masahiko

AU - Kumai, Koichiro

AU - Kitajima, Masaki

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N2 - Background: One of the target enzymes of 5-fluorouracil (5-FU) is thymidylate synthetase (TS). The DNA sequence of the TS gene includes either double or triple tandem 28-bp repeats within the promoter region, such that TS genotypes can be classified as homozygous 3R/3R, heterozygous 2R/3R or homozygous 2R/2R. Several recent studies have shown that TS genotype affects mRNA expression, with 3R/3R homozygotes showing higher TS mRNA expression compared to the other genotypes. Purpose: We analyzed the TS genotype TS and dihydropyrimidine dehydrogenase (DPD) mRNA expression levels in 22 advanced gastric carcinoma patients, and analyzed results with respect to patient 5-FU chemosensitivity, as detected by the tetrazolium-based colorimetric (MTT) assay and survival outcome. Patients and Methods: Between September 2001 and April 2002, 22 Japanese patients with advanced gastric carcinoma were evaluated. Informed written consent was obtained from all patients and the study was approved by the ethical committee at our University Hospital Fresh surgical specimens from carcinoma lesions were enzymatically dissociated and incubated with 5-FU at a concentration of 50 μg/ml for 48 hours to determine the inhibition rate as detected by MTT assay. Normal and tumor tissue and peripheral blood samples were collected and stored at -80 °C until assay for TS genotype and TS and DPD mRNA level. The TS genotype was assessed by PCR assay using peripheral monocytes, since monocyte genotypes represent the genotype of normal and tumor tissues. Quantification of TS and DPD mRNA levels was performed using real-time PCR Survival outcome was assessed according to the disease-free survival period in cases with similar clinical backgrounds. Results: TS genotyping revealed 19 3R/3R homozygotes and 32R/3R heterozygotes. After analysis of normal and tumor tissues, samples from homozygote 3R/3R cases showed higher TS mRNA expression than heterozygote 2R/3R cases, which was statistically significant at p<0.05. We also observed a statistically significant correlation in TS mRNA levels between normal and tumor tissues, while no significant correlation was observed for DPD mRNA levels between normal and tumor tissues. While no relationship between 5-FU chemosensitivity and TS genotype or mRNA expression was observed, cases with high DPD mRNA expression were resistant to 5-FU and exhibited poor survival outcomes. Conclusion: While TS genotype affected TS mRNA expression in both normal and tumor tissues in advanced gastric cancer, there is no relationship between TS genotype or mRNA expression level and 5-FU chemosensitivity. Conclusion: Our finding, that DPD mRNA expression appears to be a factor in determining 5-FU chemosensitivity and the survival outcome of advanced gastric cancer patients, is comparable with previous reports.

AB - Background: One of the target enzymes of 5-fluorouracil (5-FU) is thymidylate synthetase (TS). The DNA sequence of the TS gene includes either double or triple tandem 28-bp repeats within the promoter region, such that TS genotypes can be classified as homozygous 3R/3R, heterozygous 2R/3R or homozygous 2R/2R. Several recent studies have shown that TS genotype affects mRNA expression, with 3R/3R homozygotes showing higher TS mRNA expression compared to the other genotypes. Purpose: We analyzed the TS genotype TS and dihydropyrimidine dehydrogenase (DPD) mRNA expression levels in 22 advanced gastric carcinoma patients, and analyzed results with respect to patient 5-FU chemosensitivity, as detected by the tetrazolium-based colorimetric (MTT) assay and survival outcome. Patients and Methods: Between September 2001 and April 2002, 22 Japanese patients with advanced gastric carcinoma were evaluated. Informed written consent was obtained from all patients and the study was approved by the ethical committee at our University Hospital Fresh surgical specimens from carcinoma lesions were enzymatically dissociated and incubated with 5-FU at a concentration of 50 μg/ml for 48 hours to determine the inhibition rate as detected by MTT assay. Normal and tumor tissue and peripheral blood samples were collected and stored at -80 °C until assay for TS genotype and TS and DPD mRNA level. The TS genotype was assessed by PCR assay using peripheral monocytes, since monocyte genotypes represent the genotype of normal and tumor tissues. Quantification of TS and DPD mRNA levels was performed using real-time PCR Survival outcome was assessed according to the disease-free survival period in cases with similar clinical backgrounds. Results: TS genotyping revealed 19 3R/3R homozygotes and 32R/3R heterozygotes. After analysis of normal and tumor tissues, samples from homozygote 3R/3R cases showed higher TS mRNA expression than heterozygote 2R/3R cases, which was statistically significant at p<0.05. We also observed a statistically significant correlation in TS mRNA levels between normal and tumor tissues, while no significant correlation was observed for DPD mRNA levels between normal and tumor tissues. While no relationship between 5-FU chemosensitivity and TS genotype or mRNA expression was observed, cases with high DPD mRNA expression were resistant to 5-FU and exhibited poor survival outcomes. Conclusion: While TS genotype affected TS mRNA expression in both normal and tumor tissues in advanced gastric cancer, there is no relationship between TS genotype or mRNA expression level and 5-FU chemosensitivity. Conclusion: Our finding, that DPD mRNA expression appears to be a factor in determining 5-FU chemosensitivity and the survival outcome of advanced gastric cancer patients, is comparable with previous reports.

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KW - Gastric cancer

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KW - Thymidylate synthetase

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