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01.12.2008 | Original Article

High intratumoral dihydropyrimidine dehydrogenase mRNA levels in pancreatic cancer associated with a high rate of response to S-1

verfasst von: Hidekazu Kuramochi, Kazuhiko Hayashi, Kazumi Uchida, Go Nakajima, Takashi Hatori, Kathleen D. Danenberg, Peter V. Danenberg, Masakazu Yamamoto

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 1/2008

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Abstract

Purpose

Although the prognosis in patients with pancreatic cancer has been poor, we recently reported unusually high response rate and survival benefit of S-1 treatment in patients with pancreatic cancer. The aim of this study was to reveal genetic background of this unique activity of S-1 against pancreatic cancer. S-1 is a novel oral fluoropyrimidine derivative consisting of Tegafur (FT) and dihydropyrimidine dehydrogenase (DPD) inhibitor (5-chloro-2,4-dihydroxypyridine; CDHP). Accordingly, intratumoral DPD mRNA expression level was measured to reveal whether the level in pancreatic cancer was different from other GI cancer and whether it was relevant to chemosensitivity.

Methods

Thirty-three recurrent pancreatic cancer patients treated with S-1 were studied. We obtained 15 responders and 13 non-responders according to the change of serum CA19-9. The mRNA was extracted from paraffin-embedded surgical specimens using laser captured microdissection, and relative expression levels of each DPD/β-actin were measured using a quantitative reverse transcription polymerase chain reaction (RT-PCR) (Taqman) system. Forty-four colorectal cancer patients and 20 gastric cancer patients treated with S-1 were enrolled as control groups. Thymidylate synthase (TS) mRNA expression levels were also measured.

Results

Intratumoral DPD mRNA expression level was significantly higher in pancreatic cancer than that in colorectal cancer (P = 0.0003; median level, 1.38 vs. 0.44) and gastric cancer (P = 0.0061; 1.38 vs. 0.82). No difference in TS mRNA expression levels was observed among cancer types. DPD expression among responded pancreatic cancer was significantly lower than non-responded. (P = 0.012, Mann–Whitney U test).

Conclusions

Intratumoral DPD mRNA expression level in pancreatic cancer was significantly higher than the other malignancies. This result may elucidate possible reasons for the high effectiveness of S-1 in pancreatic cancer.

Anonymous (1992) Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-analysis Project. J Clin Oncol 10:896–903

Baccanari DP, Davis ST, Knick VC, Spector T (1993) 5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil. Proc Natl Acad Sci U S A 90:11064–11068PubMedCrossRef

Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413PubMed

Crown J, Casper ES, Botet J, Murray P, Kelsen DP (1991) Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma. J Clin Oncol 9:1682–1686PubMed

Cullinan S, Moertel CG, Wieand HS, Schutt AJ, Krook JE, Foley JF, Norris BD, Kardinal CG, Tschetter LK, Barlow JF (1990) A phase III trial on the therapy of advanced pancreatic carcinoma. Evaluations of the Mallinson regimen and combined 5-fluorouracil, doxorubicin, and cisplatin. Cancer 65:2207–2212PubMedCrossRef

de Gramont A, Bosset JF, Milan C, Rougier P, Bouche O, Etienne PL, Morvan F, Louvet C, Guillot T, Francois E, Bedenne L (1997) Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 15:808–815PubMed

DeCaprio JA, Mayer RJ, Gonin R, Arbuck SG (1991) Fluorouracil and high-dose leucovorin in previously untreated patients with advanced adenocarcinoma of the pancreas: results of a phase II trial. J Clin Oncol 9:2128–2133PubMed

Glimelius B, Hoffman K, Graf W, Pahlman L, Sjoden PO (1994) Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer. The Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Cancer 73:556–562PubMedCrossRef

Hansen R, Quebbeman E, Ritch P, Chitambar C, Anderson T (1988) Continuous 5-fluorouracil (5FU) infusion in carcinoma of the pancreas: a phase II study. Am J Med Sci 295:91–93PubMedCrossRef

10.

Hayashi K, Imaizumi T, Uchida K, Kuramochi H, Takasaki K (2002) High response rates in patients with pancreatic cancer using the novel oral fluoropyrimidine S-1. Oncol Rep 9:1355–1361PubMed

11.

Heid CA, Stevens J, Livak KJ, Williams PM (1996) Real time quantitative PCR. Genome Res 6:986–994PubMedCrossRef

12.

Hirata K, Horikoshi N, Aiba K, Okazaki M, Denno R, Sasaki K, Nakano Y, Ishizuka H, Yamada Y, Uno S, Taguchi T, Shirasaka T (1999) Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug. Clin Cancer Res 5:2000–2005PubMed

13.

Ichikawa W, Takahashi T, Suto K, Yamashita T, Nihei Z, Shirota Y, Shimizu M, Sasaki Y, Hirayama R (2004) Thymidylate synthase predictive power is overcome by irinotecan combination therapy with S-1 for gastric cancer. Br J Cancer 91:1245–1250PubMedCrossRef

14.

Kamoshida S, Shiogama K, Shimomura R, Inada K, Sakurai Y, Ochiai M, Matuoka H, Maeda K, Tsutsumi Y (2005) Immunohistochemical demonstration of fluoropyrimidine-metabolizing enzymes in various types of cancer. Oncol Rep 14:1223–1230PubMed

15.

Kuramochi H, Hayashi K, Uchida K, Miyakura S, Shimizu D, Vallbohmer D, Park S, Danenberg KD, Takasaki K, Danenberg PV (2006) 5-fluorouracil-related gene expression levels in primary colorectal cancer and corresponding liver metastasis. Int J Cancer 119:522–526PubMedCrossRef

16.

Lord RV, Salonga D, Danenberg KD, Peters JH, DeMeester TR, Park JM, Johansson J, Skinner KA, Chandrasoma P, DeMeester SR, Bremner CG, Tsai PI, Danenberg PV (2000) Telomerase reverse transcriptase expression is increased early in the Barrett’s metaplasia, dysplasia, adenocarcinoma sequence. J Gastrointest Surg 4:135–142PubMedCrossRef

17.

Mori K, Hasegawa M, Nishida M, Toma H, Fukuda M, Kubota T, Nagasue N, Yamana H, Hirakawa YSCK, Ikeda T, Takasaki K, Oka M, Kameyama M, Toi M, Fujii H, Kitamura M, Murai M, Sasaki H, Ozono S, Makuuchi H, Shimada Y, Onishi Y, Aoyagi S, Mizutani K, Ogawa M, Nakao A, Kinoshita H, Tono T, Imamoto H, Nakashima Y, Manabe T (2000) Expression levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in various human tumor tissues. Int J Oncol 17:33–38PubMed

18.

Nishimura G, Yanoma S, Mizuno H, Satake K, Taguchi T, Ikeda Y, Tsukuda M (2000) Therapeutic effect of 1 M tegafur-0.4 M 5-chloro-2, 4-dihydroxypridine-1 M potassium oxonate (S-1) on head and neck squamous carcinoma cells. Cancer Lett 159:1–7PubMedCrossRef

19.

Nitecki SS, Sarr MG, Colby TV, van Heerden JA (1995) Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg 221:59–66PubMedCrossRef

20.

Ohtsu A, Baba H, Sakata Y, Mitachi Y, Horikoshi N, Sugimachi K, Taguchi T (2000) Phase II study of S-1, a novel oral fluorophyrimidine derivative, in patients with metastatic colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study Group. Br J Cancer 83:141–145PubMedCrossRef

21.

Poon MA, O’Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK, et al (1989) Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7:1407–1418PubMed

22.

Saek T, Takashima S, Sano M, Horikoshi N, Miura S, Shimizu S, Morimoto K, Kimura M, Aoyama H, Ota J, Noguchi S, Taguchi T (2004) A phase II study of S-1 in patients with metastatic breast cancer—a Japanese trial by the S-1 Cooperative Study Group, Breast Cancer Working Group. Breast Cancer 11:194–202PubMedCrossRef

23.

Sakata Y, Ohtsu A, Horikoshi N, Sugimachi K, Mitachi Y, Taguchi T (1998) Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patients. Eur J Cancer 34:1715–1720PubMedCrossRef

24.

Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, Fukushima M (1996) Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 7:548–557PubMedCrossRef

25.

Takechi T, Fujioka A, Matsushima E, Fukushima M (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 38:1271–1277PubMedCrossRef

26.

Tatsumi K, Fukushima M, Shirasaka T, Fujii S (1987) Inhibitory effects of pyrimidine, barbituric acid and pyridine derivatives on 5-fluorouracil degradation in rat liver extracts. Jpn J Cancer Res 78:748–755PubMed

27.

Uetake H, Ichikawa W, Takechi T, Fukushima M, Nihei Z, Sugihara K (1999) Relationship between intratumoral dihydropyrimidine dehydrogenase activity and gene expression in human colorectal cancer. Clin Cancer Res 5:2836–2839PubMed

Titel: High intratumoral dihydropyrimidine dehydrogenase mRNA levels in pancreatic cancer associated with a high rate of response to S-1
verfasst von: Hidekazu Kuramochi
Kazuhiko Hayashi
Kazumi Uchida
Go Nakajima
Takashi Hatori
Kathleen D. Danenberg
Peter V. Danenberg
Masakazu Yamamoto
Publikationsdatum: 01.12.2008
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 1/2008
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-008-0714-x

Springer Medizin

High intratumoral dihydropyrimidine dehydrogenase mRNA levels in pancreatic cancer associated with a high rate of response to S-1