Comparative analysis of thymidine phosphorylase and dihydropyrimidine dehydrogenase expression in gastric and colorectal cancers

Hotta, Tsukasa; Taniguchi, K; Kobayashi, Yasuhito; Johata, Kiyofumi; Sahara, Masaki; Naka, Teiji; Watanabe, Takashi; Ochiai, Minoru; Tanimura, Hiroshi; Tsubota, Yuji

doi:10.3892/or.11.5.1045

Cited by 7 publications

(10 citation statements)

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“…It has been previously reported that DPD had lower expression in primary tumor rather than adjacent uninvolved normal tissues in CRC, 7,21,22 ovarian cancer 23 and gastric cancer. 24 Our data are consistent with these results. In contrast, most previous studies have reported that TP has higher expression in primary tumor than in adjacent normal tissue, [22][23][24] a concept that was used as the main rationale for the design of Xeloda (capecitabine), which was thereby expected to be selectively activated in tumors by the action of TP.…”

Section: Discussionsupporting

confidence: 83%

“…24 Our data are consistent with these results. In contrast, most previous studies have reported that TP has higher expression in primary tumor than in adjacent normal tissue, [22][23][24] a concept that was used as the main rationale for the design of Xeloda (capecitabine), which was thereby expected to be selectively activated in tumors by the action of TP. However, in contrast to these earlier studies, we found that TP expression was lower both in primary colorectal tumor and liver metastatic tumor than in adjacent normal tissues.…”

Section: Discussionsupporting

confidence: 83%

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5‐fluorouracil‐related gene expression levels in primary colorectal cancer and corresponding liver metastasis

Kuramochi

Hayashi

Uchida

et al. 2006

Intl Journal of Cancer

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Gene expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyl transferase (OPRT) have been shown to be associated with response to 5-fluorouracil-based therapies. Analyzing these gene expression levels in liver metastases is important to obtain the best prediction of therapy. Our aim was to determine how TS, DPD, TP and OPRT gene expression levels in primary colorectal cancer (CRC) were related to those in liver metastases. Formalin-fixed, paraffin-embedded tumor specimens from 31 pairs of primary CRC and corresponding liver metastases were dissected by using laser-captured microdissection. RNA was extracted and cDNA was prepared by reverse-transcription. Quantitation of target gene and internal reference gene was performed using real-time PCR. No significant difference was seen between median mRNA expression levels of TS, DPD, TP and OPRT in primary cancer and those in corresponding liver metastases (median value: TS 1.48 vs. When matched tissue sets were compared on an individual basis, there was a significant correlation for TS mRNA expression between primary cancer and corresponding liver metastases (rs 5 0.52, p 5 0.0026). However, no correlation was seen between matched sets for DPD, TP or OPRT. Significant correlation was seen between DPD and TP expression levels in both primary CRC (rs 5 0.38, p 5 0.03) and liver metastases (rs 5 0.72, p < 0.0001). A good prediction of TS mRNA levels in liver metastases can be obtained by measuring those of primary CRC, although no correlation was seen for DPD, TP and OPRT. ' 2006 Wiley-Liss, Inc.Key words: 5-fluorouracil; colorectal cancer; liver metastases; thymidylate synthase; dihydropyrimidine dehydrogenase Colorectal cancer (CRC) is the fourth most common malignancy and the second leading cause of cancer death in the United States. 1 The most commonly used chemotherapeutic drug for CRC is 5-fluorouracil (5-FU), which has been used for more than 40 years and still remains an important component of many standard treatments. 2 The main mechanism of 5-FU activity involves inhibition of thymidylate synthase (TS), which is the rate-limiting enzyme in the synthesis of thymine nucleotides.A number of genes have been investigated as predictive factors for response to 5-FU-related drugs and as prognostic markers. Leichman et al. 3 had previously shown that high gene expression levels (mRNA levels) of TS identified tumors that would be nonresponsive to 5-FU based therapy. Dihydropyrimidine dehydrogenase (DPD) is responsible for the degradation of the pyrimidines, uracil and thymine, as well as the inactivation of the 5-FU, and has been shown in several studies to be associated with response to 5-FU-based therapies. [4][5][6][7] Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor, has a role in tumor angiogenesis but also catalyzes the conversion of 5-FU to the more active nucleoside form and has been shown to be an in vitro determinant of 5-FU activity...

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 83%

5‐fluorouracil‐related gene expression levels in primary colorectal cancer and corresponding liver metastasis

Kuramochi

Hayashi

Uchida

et al. 2006

Intl Journal of Cancer

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“…In a study of gastric cancer patients, the survival rate of those who received postoperative 5′-DFUR therapy was better in the group that had a higher TP/DPD ratio [25]. In contrast, higher TP/DPD ratios have been implicated in decreased survival in some studies [13,27]. Miyake et al observed that the PC patients with a lower TP/DPD ratio had much better survival compared to those with a higher TP/DPD ratio even after adjusting for the tumor characteristics [13].…”

Section: Discussionmentioning

confidence: 94%

Prognostication of pancreatic adenocarcinoma by expression of thymidine phosphorylase/dihydropyrimidine dehydrogenase ratio and its correlation with survival

Saif

Hashmi

Bell

et al. 2009

Expert Opinion on Drug Safety

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We found a survival benefit of approximately 4 months in our study correlating with lower TP/DPD ratio and this is quite significant in a disease whose > 5-year survival is < 5%. The TP/DPD ratio may be used as an independent marker for prognostication for LAPC and it may help in determining the chemotherapy duration, choices and possibly toxicities as well. Larger studies are needed to study the relation ship between TP/DPD ratio with these efficacy parameters.

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“…It has been reported that DPD mRNA, but not DPD activity, is reduced in colorectal tumours compared with normal mucosa, although considerable overlap exists in measured mRNA levels. [103][104][105][106][107][108][109][110] Reduced mRNA levels have also been reported in ovarian cancer. 111 DPD activity appears to be increased in breast cancer (see Table 3).…”

Section: -Fluorouracilmentioning

confidence: 99%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumourspecific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5 0 -nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

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Comparative analysis of thymidine phosphorylase and dihydropyrimidine dehydrogenase expression in gastric and colorectal cancers

Cited by 7 publications

References 0 publications

5‐fluorouracil‐related gene expression levels in primary colorectal cancer and corresponding liver metastasis

5‐fluorouracil‐related gene expression levels in primary colorectal cancer and corresponding liver metastasis

Prognostication of pancreatic adenocarcinoma by expression of thymidine phosphorylase/dihydropyrimidine dehydrogenase ratio and its correlation with survival

Genetic factors influencing Pyrimidine-antagonist chemotherapy

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