Thymidylate synthase and dihydropyrimidine dehydrogenase mRNA expression levels: Predictors for survival in colorectal cancer patients receiving adjuvant 5-fluorouracil

Despite adjuvant 5-fluorouracil (5-FU) therapy, approximately 30% of patients with International Union against Cancer stage II and III colorectal cancer develop recurrence. In this study, we determined the prognostic value of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) expres...

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Bibliographic Details
Published in:Clinical cancer research 2003-09, Vol.9 (11), p.4116-4124
Main Authors: KORNMANN, Marko, SCHWABE, Wolfgang, HÄUSLER, Peter, OTT, Kati, BEHNKE, Detlev, STAIB, Ludger, BEGER, Hans G, LINK, Karl H, SANDER, Silvia, KRON, Martina, STRÄTER, Jörn, POLAT, Sucan, KETTNER, Erika, WEISER, Hans F, BAUMANN, Wolfram, SCHRAMM, Harald
Format: Article
Language:English
Subjects:
Aged
Antimetabolites, Antineoplastic - therapeutic use
Biological and medical sciences
Chemotherapy, Adjuvant
Colonic Neoplasms - drug therapy
Colonic Neoplasms - mortality
Dihydrouracil Dehydrogenase (NADP) - genetics
Female
Fluorouracil - therapeutic use
Gastroenterology. Liver. Pancreas. Abdomen
Gene Expression Regulation, Neoplastic - genetics
Humans
Immunohistochemistry
Male
Medical sciences
Middle Aged
Prognosis
Rectal Neoplasms - drug therapy
Rectal Neoplasms - mortality
RNA, Messenger - genetics
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Survival Analysis
Thymidylate Synthase - metabolism
Transcription, Genetic - genetics
Tumors
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Summary:Despite adjuvant 5-fluorouracil (5-FU) therapy, approximately 30% of patients with International Union against Cancer stage II and III colorectal cancer develop recurrence. In this study, we determined the prognostic value of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) expression in colorectal cancer patients treated with adjuvant 5-FU. A real-time reverse transcription-PCR technique for quantitation of relative gene expression from paraffin-embedded specimen was established first. In a second step, archival paraffin-embedded primary tumor tissue of 309 patients who participated in adjuvant colorectal cancer trials was analyzed for TS and DPD mRNA expression. TS mRNA expression determined by real-time reverse transcription-PCR correlated with TS protein levels determined by TS immunoblot and immunohistochemistry in cultured colon cancer cell lines and paraffin-embedded primary tumor tissue. TS mRNA levels in fresh-frozen tissues also correlated with TS mRNA levels in corresponding paraffin sections. Among the patients receiving adjuvant 5-FU therapy, those with high TS survived longer than those with low TS, and in each TS subgroup, the ones with low DPD survived longer than the ones with high DPD levels. Multiple Cox regression analysis showed that besides tumor stage (P = 0.010), only the combination of TS and DPD expression turned out to be an independent prognostic factor for survival (P = 0.030). This suggests that TS and DPD quantitation may be helpful to evaluate prognosis of patients receiving adjuvant 5-FU and that patients with high TS and low DPD may benefit from adjuvant 5-FU chemotherapy.
ISSN:1078-0432
1557-3265