Thymidylate Synthase Gene Expression in Primary Colorectal Cancer and Metastatic Sites

Yamada, Hiroyuki; Ichikawa, Wataru; Uetake, Hiroyuki; Shirota, Yoshinori; Nihei, Zenro; Sugihara, Kenichi; Hirayama, Renzo

doi:10.3816/ccc.2001.n.017

Cited by 34 publications

(25 citation statements)

References 14 publications

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“…In the present study, however, the TS mRNA level did not differ between metastatic liver tumors and primary colorectal cancer, and did not correlate with sensitivity to 5-FU in both the clinical samples and animal model. Previous reports have indicated that the expression level of TS mRNA or protein in liver metastases is significantly lower than that of primary colorectal cancer (20,21). These reports also indicate that TS might not influence the acquisition of resistance to 5-FU during liver metastases of colorectal cancer.…”

Section: Discussionmentioning

confidence: 71%

“…Several 5-FU-related metabolic enzymes have been studied, and their intratumoral expression levels are thought to correlate with sensitivity to 5-FU (4-10,19). Some reports have indicated that the expression levels of 5-FU metabolic enzymes differed between the primary and metastatic sites (20,21). In this study, we focused on 5-FU-related metabolic enzymes.…”

Section: Discussionmentioning

confidence: 98%

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Correlation between chemosensitivity and mRNA expression level of 5-fluorouracil-related metabolic enzymes during liver metastasis of colorectal cancer

Okumura

Shiomi²,

Mekata³

et al. 2006

Oncol Rep

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Abstract. The attainment of chemoresistance during tumor metastasis is often experienced. In this study, we evaluated the correlation between sensitivity to 5-fluorouracil (5-FU) and the mRNA expression level of several 5-FU-related metabolic enzymes [thymidylate synthase, dihydropyrimidine dehydrogenase (DPD), thymidylate phosphorylase (TP), orotate phosphoribosyl transferase, and uridine phosphorylase] in primary colorectal cancer and synchronous liver metastases from ten patients to investigate how colorectal cancer acquires 5-FU resistance during liver metastases. A liver metastasis model of xenotransplanted human colon cancer cell line (HCT116) in nude mice and several cell lines from metastatic liver tumors were also established and analyzed. Chemosensitivity and mRNA expression levels were measured by using collagen gel droplet-embedded culture drug sensitivity tests and real-time quantitative reverse transcriptionpolymerase chain reaction. Metastatic liver tumors were significantly more resistant to 5-FU than primary colorectal cancer (T/C, 88.7% versus 69.7%, p<0.05). DPD and TP mRNA levels were significantly higher in metastatic liver tumors (DPD: 10.36±1.81 versus 3.95±0.99, p<0.01; and TP: 18.80±4.96 versus 7.28±1.23, p<0.05) and inversely correlated with 5-FU sensitivity (DPD: R=0.570, p<0.05; TP: R=0.600, p<0.05). In the mouse model, metastatic liver tumors were significantly more resistant to 5-FU than HCT116 (T/C, 92.7%, 96.2% versus 68%, p<0.001). The DPD and TP mRNA levels increased with repeated liver metastases. DPD and TP may affect the acquisition of resistance to 5-FU during liver metastasis of colorectal cancer. This mouse model may be useful for analyzing the mechanisms of how colorectal cancer acquires resistance to 5-FU during liver metastases.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 98%

Correlation between chemosensitivity and mRNA expression level of 5-fluorouracil-related metabolic enzymes during liver metastasis of colorectal cancer

Okumura

Shiomi²,

Mekata³

et al. 2006

Oncol Rep

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“…However, only a few studies have been done on this important issue. Yamada et al reported that TS gene expression was higher in primary CRCs than in liver metastases, 12 whereas Backus et al showed opposite results in TS protein level. 13 DPD gene expression levels were reported to be lower in primary cancers than in liver metastases in several studies, 14,15 whereas another report found that DPD activity in liver metastases was not significantly different from that observed in primary colon tumors.…”

mentioning

confidence: 99%

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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“…40 Recent studies have found that TS levels measured in primary tumours do not correspond with those measured in the corresponding metastasis. 41,42 For example, in matched samples of primary and metastatic…”

Section: -Fluorouracil (5fu)mentioning

confidence: 99%

“…41 These results may explain why TS expression in primary tumour samples may not predict response of metastases to treatment. 43 Thymidine phosphorylase (TP) reversibly converts 5FU to its active metabolite FdUMP.…”

Section: -Fluorouracil (5fu)mentioning

confidence: 99%

Clinical significance of prognostic and predictive markers in colorectal cancer

2002

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Thymidylate Synthase Gene Expression in Primary Colorectal Cancer and Metastatic Sites

Cited by 34 publications

References 14 publications

Correlation between chemosensitivity and mRNA expression level of 5-fluorouracil-related metabolic enzymes during liver metastasis of colorectal cancer

Correlation between chemosensitivity and mRNA expression level of 5-fluorouracil-related metabolic enzymes during liver metastasis of colorectal cancer

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

Clinical significance of prognostic and predictive markers in colorectal cancer

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