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International Journal of Clinical Oncology

Erschienen in:

01.02.2010 | Original Article

Clinical significance of dihydropyrimidine dehydrogenase and thymidylate synthase expression in patients with pancreatic cancer

verfasst von: Osamu Nakahara, Hiroshi Takamori, Hiroshi Tanaka, Yasuo Sakamoto, Yoshiaki Ikuta, Satoshi Furuhashi, Masayuki Watanabe, Toru Beppu, Masahiko Hirota, Keiichiro Kanemitsu, Hideo Baba

Erschienen in: International Journal of Clinical Oncology | Ausgabe 1/2010

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Abstract

Background

Little is known about the clinical significance of TS and DPD in pancreatic cancer. We aimed to evaluate TS and DPD expression levels in not only pancreatic cancer but also surrounding normal pancreatic tissues to assess the clinical implications of the expression of TS and DPD in this study.

Patients and methods

Pancreatic cancer and normal pancreatic tissues were obtained from 18 patients with pancreatic cancer who underwent pancreatic resection to measure TS and DPD activities. The TS and DPD activities were determined by enzyme-linked immunosorbent assay using non-fixed fresh-frozen specimens.

Results

Pancreatic cancer tissues had significantly higher DPD and TS enzyme activities than surrounding normal tissue. Anaplastic ductal carcinoma had higher DPD and TS activities than the other histological types. Patients with high DPD in this study demonstrated poorer prognosis than those with low DPD. On the other hand, there was no statistically significant difference in survival between the high and the low TS groups.

Conclusions

The efficacy of 5-FU may be lower in pancreatic cancer tissue than in normal tissue because DPD activity is upregulated in pancreatic cancer tissue compared to normal pancreatic tissue. It is necessary to develop an effective 5-FU delivery system and/or 5-FU combined with an inhibitor for DPD that can be used when 5-FU must be administered to patients with pancreatic cancer. High DPD activity may be a prognostic factor in patients with pancreatic cancer.

Silverman DT, Schiffman M, Everhart J et al (1999) Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer. Br J Cancer 80:1830–1837CrossRefPubMed

Lockhart AC, Rothenberg ML, Berlin JD (2005) Treatment for pancreatic cancer: current therapy and continued progress. Gastroenterology 128:1642–1654CrossRefPubMed

Ries L, Harkins D, Krapcho M, Mariotto A, Miller BA, Feuer EJ, Clegg L, Eisner MP, Horner MJ, Howlader N, Hayat M, Hankey BF, Edwards BK (eds) (2006) SEER cancer statistics review, 1975–2003. National Cancer Institute, Bethesda (based on November 2005 SEER data submission, posted to the SEER website; cited 21 Nov 2007)

Sener SF, Fremgen A, Menck HR et al (1999) Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985–1995, using the National Cancer Database. J Am Coll Surg 189:1–7CrossRefPubMed

Sperti C, Pasquali C, Piccoli A et al (1997) Recurrence after resection for ductal adenocarcinoma of the pancreas. World J Surg 21:195–200CrossRefPubMed

Griffin JF, Smalley SR, Jewell W et al (1990) Patterns of failure after curative resection of pancreatic carcinoma. Cancer 66:56–61CrossRefPubMed

Westerdahl J, Andren-Sandberg A, Ihse I (1993) Recurrence of exocrine pancreatic cancer—local or hepatic? Hepatogastroenterology 40:384–387PubMed

Beck A, Etienne MC, Cheradame S et al (1994) A role for dihydropyrimidine dehydrogenase and thymidylate synthase in tumour sensitivity to fluorouracil. Eur J Cancer 30A:1517–1522CrossRefPubMed

Ota D, Kusama M, Kaise H et al (2004) Evaluation of sensitivity to 5-FU on the basis of thymidylate synthase (TS)/dihydropyrimidine dehydrogenase (DPD) activity and chromosomal analysis in micro tissue specimens of breast cancer. Breast Cancer (Tokyo, Japan) 11:356–366

10.

Ichikawa W, Takahashi T, Suto K et al (2004) Thymidylate synthase predictive power is overcome by irinotecan combination therapy with S-1 for gastric cancer. Br J Cancer 91:1245–1250CrossRefPubMed

11.

Vallbohmer D, Yang DY, Kuramochi H et al (2007) DPD is a molecular determinant of capecitabine efficacy in colorectal cancer. Int J Oncol 31:413–418PubMed

12.

Kobayashi H, Koike T, Nakatsuka A et al (2005) Dihydropyrimidine dehydrogenase expression predicts survival outcome and chemosensitivity to 5-fluorouracil in patients with oral squamous cell carcinoma. Oral Oncol 41:38–47CrossRefPubMed

13.

Tsuji T, Sawai T, Takeshita H et al (2004) Tumor dihydropyrimidine dehydrogenase expression is a useful marker in adjuvant therapy with oral fluoropyrimidines after curative resection of colorectal cancer. Cancer Chemother Pharmacol 54:531–536CrossRefPubMed

14.

Japan Pancreas Society (2003) Classification of pancreatic cancer, 2nd English edn. Kanehara & Co. Ltd., Tokyo, pp 4–12

15.

Spears CP, Shahinian AH, Moran RG et al (1982) In vivo kinetics of thymidylate synthetase inhibition of 5-fluorouracil-sensitive and -resistant murine colon adenocarcinomas. Cancer Res 42:450–456PubMed

16.

Naguib FN, el Kouni MH, Cha S (1985) Enzymes of uracil catabolism in normal and neoplastic human tissues. Cancer Res 45:5405–5412PubMed

17.

Takechi T, Fujioka A, Matsushima E et al (2002) Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2, 4-dihydroxypyridine (CDHP) in human tumour cells. Eur J Cancer 38:1271–1277CrossRefPubMed

18.

Maring JG, Groen HJ, Wachters FM et al (2005) Genetic factors influencing pyrimidine-antagonist chemotherapy. Pharmacogenomics J 5:226–243CrossRefPubMed

19.

Kuramochi H, Hayashi K, Uchida K et al (2008) High intratumoral dihydropyrimidine dehydrogenase mRNA levels in pancreatic cancer associated with a high rate of response to S-1. Cancer Chemother Pharmacol 63:85–89CrossRefPubMed

20.

Kamoshida S, Shiogama K, Shimomura R et al (2005) Immunohistochemical demonstration of fluoropyrimidine-metabolizing enzymes in various types of cancer. Oncol Rep 14(5):1223–1230PubMed

21.

Fukushima M, Morita M, Ikeda K et al (2003) Population study of expression of thymidylate synthase and dihydropyrimidine dehydrogenase in patients with solid tumors. Int J Mol Med 12:839–844PubMed

22.

Takamori H, Kanemitsu K, Tsuji T et al (2005) 5-fluorouracil intra-arterial infusion combined with systemic gemcitabine for unresectable pancreatic cancer. Pancreas 30:223–226CrossRefPubMed

23.

Shimizu T, Yamada Y, Yasui H et al (2005) Clinical application of immunoreactivity of dihydropyrimidine dehydrogenase (DPD) in gastric scirrhous carcinoma treated with S-1, a new DPD inhibitory fluoropyrimidine. Anticancer Res 25:2997–3001PubMed

24.

Mizutani Y, Wada H, Fukushima M et al (2001) The significance of dihydropyrimidine dehydrogenase (DPD) activity in bladder cancer. Eur J Cancer 37:569–575CrossRefPubMed

25.

Miyake K, Imura S, Yoshizumi T et al (2007) Role of thymidine phosphorylase and orotate phosphoribosyltransferase mRNA expression and its ratio to dihydropyrimidine dehydrogenase in the prognosis and clinicopathological features of patients with pancreatic cancer. Int J Clin Oncol 12(2):111–119CrossRefPubMed

26.

Edler D, Kressner U, Ragnhammar P et al (2000) Immunohistochemically detected thymidylate synthase in colorectal cancer: an independent prognostic factor of survival. Clin Cancer Res 6:488–492PubMed

27.

Lenz HJ, Leichman CG, Danenberg KD et al (1996) Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J Clin Oncol 14:176–182PubMed

28.

Harpole DH Jr, Moore MB, Herndon JE 2nd et al (2001) The prognostic value of molecular marker analysis in patients treated with trimodality therapy for esophageal cancer. Clin Cancer Res 7:562–569PubMed

29.

Romain S, Spyratos F, Descotes F et al (2000) Prognostic of DNA-synthesizing enzyme activities (thymidine kinase and thymidylate synthase) in 908 T1–T2, N0–N1, M0 breast cancers: a retrospective multicenter study. Int J Cancer 87:860–868CrossRefPubMed

30.

Harada K, Kawashima Y, Yoshida H et al (2006) Thymidylate synthase expression in oral squamous cell carcinoma predicts response to S-1. Oncol Rep 15:1417–1423PubMed

31.

Hu YC, Komorowski RA, Graewin S et al (2003) Thymidylate synthase expression predicts the response to 5-fluorouracil-based adjuvant therapy in pancreatic cancer. Clin Cancer Res 9:4165–4171PubMed

32.

Formentini A, Sander S, Denzer S et al (2007) Thymidylate synthase expression in resectable and unresectable pancreatic cancer: role as predictive or prognostic marker? Int J Colorectal Dis 22:49–55CrossRefPubMed

Titel: Clinical significance of dihydropyrimidine dehydrogenase and thymidylate synthase expression in patients with pancreatic cancer
verfasst von: Osamu Nakahara
Hiroshi Takamori
Hiroshi Tanaka
Yasuo Sakamoto
Yoshiaki Ikuta
Satoshi Furuhashi
Masayuki Watanabe
Toru Beppu
Masahiko Hirota
Keiichiro Kanemitsu
Hideo Baba
Publikationsdatum: 01.02.2010
Verlag: Springer Japan
Erschienen in: International Journal of Clinical Oncology / Ausgabe 1/2010
Print ISSN: 1341-9625
Elektronische ISSN: 1437-7772
DOI: https://doi.org/10.1007/s10147-009-0008-2

Springer Medizin

Clinical significance of dihydropyrimidine dehydrogenase and thymidylate synthase expression in patients with pancreatic cancer