Expression levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in various human tumor tissues.

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...

Section: Discussioncontrasting

confidence: 51%

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

Kuramochi

Hayashi

Uchida

et al. 2006

“…The present study, in keeping with other biochemical 28 and immunohistochemical studies, 13,14,19 shows that TP expression is upregulated in the cells of human breast carcinoma. Our present data show a high incidence of TP-positive breast carcinomas, which is higher than the one described by Fox et al 13 ; this could be ascribed to the different antibodies used in the 2 studies and to the different scoring systems and cut-off points adopted.…”

Section: Discussionsupporting

confidence: 91%

Prognostic value of thymidine phosphorylase expression in breast carcinoma

Yang

Barbareschi

Mori

et al. 2001

Thymidine phosphorylase (TP), also known as plateletderived endothelial cell growth factor (PD-ECGF), is an enzyme that catalyzes the reversible dephosphorylation of thymidine, deoxyuridine and their analogs. TP has also angiogenic properties, although the precise mechanism by which it promotes angiogenesis is not known. We examined TP expression using immunohistochemistry (654- Thymidine phosphorylase (TP) is an enzyme specifically involved in the reversible dephosphorylation of thymidine, deoxyuridine and their analogs to their respective bases and 2-deoxy-Dribose-1-phosphate. 1 TP is also able to catalyze the conversion of the pyrimidine antimetabolite 5-fluorouracil (5-FU) to 5-fluoro-2Ј-deoxyuridine, the first step in 1 of the metabolic activation pathways of this chemotherapeutic agent to deoxyribonucleotides. 2 TP has also been identified as an angiogenic factor and identical to platelet derived endothelial cell growth factor (PD-ECGF). 3-5 TP is angiogenic in vivo and stimulates chemotaxis of endothelial cells in vitro. 6 -8 Recently, several antibodies have been generated that allow the immunohistochemical investigation of TP expression. 9,10 TP expression has been observed in many normal human tissues: the predominant cells expressing TP are macrophages, but epithelial cells stain as well. 9 Many studies have also shown that TP is upregulated in several tumor types, 9 including breast carcinomas, where it is expressed by both epithelial and stromal cells including macrophages. 11 In intraductal breast carcinomas, epithelial TP expression is correlated with the presence of a dense vascular rim around tumor cell nests, but neither with stromal vascularity nor with relapse-free survival. 12 In invasive breast cancer TP is upregulated in 39 -52% of cases, 11,13 and its relationship with vascularity is controversial: some authors report that no relationship was found between vascularity and TP expression in either the carcinoma or the inflammatory cells, 14 whereas others reported the opposite. 11 These conflicting data may reflect the complexity of the angiogenic process and may also suggest that in breast carcinogenesis TP is important in initial remodeling of the preexisting vascular network but that other factors are needed for extensive induction of vessels growth. 12 Preclinical studies have shown a correlation between fluoropyrimidine sensitivity and TP levels. Transfection experiments have provided evidence that TP mediates the sensitivity of HT-29 human colon carcinoma cells to 5-FU 15 and of several cell lines (MCF-7 human breast cancer cells, PC-9 lung adenocarcinoma cells, and KB epidermal carcinoma cells) to 5Ј-deoxy-5-fluorouridine (5Ј-DFUR), a prodrug of 5-FU. 16 -18 In the clinical setting, it has been suggested that TP may correlate with the efficacy of adjuvant therapy with 5-FU and its derivatives. 13,19,20 A recent study has also shown that high expression of TP in cell lines potentiates the effect of the cytotoxic drug methotrexate, 21 offering an additional rationale to investigate ...

“…Furthermore, some reports showed that the DPD expression level in diffuse tumor was significantly higher than that in intestinal tumor and DPD expression level correlated significantly with TP expression level, are also consistent with the results of our study. [22][23][24] Several reports have demonstrated the relationship between combined treatment, i.e., 5-FU plus cisplatin, and TS. In mammalian tumor models, cisplatin significantly enhances the antitumor effect of 5-FU by inhibiting L-methionine metabolism and consequently increasing intratumor reduced folates, which are essential cofactors for the TS inhibition.…”

Section: Discussionmentioning

confidence: 99%

Impacts of fluorouracil‐metabolizing enzymes on the outcomes of patients treated with S‐1 alone or S‐1 plus cisplatin for first‐line treatment of advanced gastric cancer

Koizumi

Tanabe

Azuma

et al. 2009

A phase III trial of S-1 plus cisplatin (SP) versus S-1 alone, for first-line treatment of advanced gastric cancer (SPIRITS trial), has shown that overall survival was better in patients treated with SP than with S-1 alone. In the present retrospective biomarker study, we aimed to develop a methodology to identify the patients with advanced gastric cancer who would respond better to S-1 alone than SP. We studied 120 patients who received S-1 alone or SP for first-line chemotherapy for advanced gastric cancer, and quantitatively evaluated mRNA levels of thymidylate synthase (TS), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase, vascular endothelial growth factor-A, and epidermal growth factor receptor in paraffin-embedded specimens of primary tumors. Multivariate survival analysis in patients who received S-1 monotherapy (66 patients) demonstrated that low TP expression (hazard ratio: 2.55 (95% CI: (1.33 to 4.89)), low TS (2.71 (1.36 to 5.37)), and high OPRT (0.33 (0.13 to 0.86)) were significant predictors of long overall survival. In patients with lower expression of both TP and TS (n 5 23) than their cutoff values, the S-1 alone group (n 5 15) had longer overall survival than the SP group (n 5 8; median overall survival, 18.2 months vs. 9.4 months), whereas the frequency of overall adverse events in the S-1 alone group tended to be lower than that in SP group. Our results suggest that these biomarkers are useful for selection of patients with advanced gastric cancer in whom treatment with S-1 alone will yield survival benefit.