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Research ArticleExperimental Studies

Pretreatment with S-1, an Oral Derivative of 5-Fluorouracil, Enhances Gemcitabine Effects in Pancreatic Cancer Xenografts

SHIN NAKAHIRA, SHOJI NAKAMORI, MASANORI TSUJIE, SETSUO TAKEDA, KEISHI SUGIMOTO, YUJI TAKAHASHI, JIRO OKAMI, SHIGERU MARUBASHI, ATSUSHI MIYAMOTO, YUTAKA TAKEDA, HIROAKI NAGANO, KEIZO DONO, KOJI UMESHITA, MASATO SAKON and MORITO MONDEN
Anticancer Research January 2008, 28 (1A) 179-186;
SHIN NAKAHIRA
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SHOJI NAKAMORI
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  • For correspondence: nakamori@onh.go.jp
MASANORI TSUJIE
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SETSUO TAKEDA
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KEISHI SUGIMOTO
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YUJI TAKAHASHI
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JIRO OKAMI
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SHIGERU MARUBASHI
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ATSUSHI MIYAMOTO
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YUTAKA TAKEDA
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HIROAKI NAGANO
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KEIZO DONO
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KOJI UMESHITA
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MASATO SAKON
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MORITO MONDEN
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Abstract

Background: The systemic administration of gemcitabine (GEM) has been accepted as a standard treatment for patients with advanced pancreatic cancer. The major mediator of cellular uptake of GEM is the human equilibrative nucleoside transporter 1 (hENT1) whose expression is up-regulated by thymidylate synthase inhibitors, such as 5-fluorouracil (5-FU). S-1 is a novel oral derivative of the 5-FU prodrug tegafur combined with two modulators. Recent clinical trials have reported the promising effect of S-1 in pancreatic cancer. The purpose of this study was to evaluate the relationship between different schedules and the effects of GEM/S-1 combination therapy on pancreatic cancer xenograft models. Materials and Methods: Human pancreatic tumor xenografts were prepared by subcutaneous implantation of MiaPaCa-2 into nude mice. Expression of hENT1 was determined by quantitative RT-PCR. GEM cellular uptake was determined using [3H] GEM. Results: Significant increases in hENT1 expression and GEM cellular uptake were observed after S-1 treatment. Six different treatment schedules (no treatment, single agent of GEM or S-1, combination treatment with GEM either before, simultaneously or following administration of S-1) were compared. Significant tumor growth inhibition was observed in the mice treated with S-1 followed by GEM compared to either untreated mice or the mice treated with the other schedules. Conclusion: Based on the effects of S-1 on the uptake of GEM, S-1 should be used before GEM treatment. The GEM/S-1 combination therapy in patients with pancreatic cancer may be promising and should be tested in clinical trials.

  • S-1
  • 5-fluorouracil
  • gemcitabine
  • human equilibrative nucleotide transporter
  • schedule-dependent effect
  • combination chemotherapy
  • in vivo
  • pancreatic cancer
  • Received June 15, 2007.
  • Revision received November 26, 2007.
  • Accepted December 17, 2007.
  • Copyright© 2008 International Institute of Anticaner Research (Dr. John G. Delinassios), All rights reserved
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Anticancer Research: 28 (1A)
Anticancer Research
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January-February 2008
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Pretreatment with S-1, an Oral Derivative of 5-Fluorouracil, Enhances Gemcitabine Effects in Pancreatic Cancer Xenografts
SHIN NAKAHIRA, SHOJI NAKAMORI, MASANORI TSUJIE, SETSUO TAKEDA, KEISHI SUGIMOTO, YUJI TAKAHASHI, JIRO OKAMI, SHIGERU MARUBASHI, ATSUSHI MIYAMOTO, YUTAKA TAKEDA, HIROAKI NAGANO, KEIZO DONO, KOJI UMESHITA, MASATO SAKON, MORITO MONDEN
Anticancer Research Jan 2008, 28 (1A) 179-186;

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Pretreatment with S-1, an Oral Derivative of 5-Fluorouracil, Enhances Gemcitabine Effects in Pancreatic Cancer Xenografts
SHIN NAKAHIRA, SHOJI NAKAMORI, MASANORI TSUJIE, SETSUO TAKEDA, KEISHI SUGIMOTO, YUJI TAKAHASHI, JIRO OKAMI, SHIGERU MARUBASHI, ATSUSHI MIYAMOTO, YUTAKA TAKEDA, HIROAKI NAGANO, KEIZO DONO, KOJI UMESHITA, MASATO SAKON, MORITO MONDEN
Anticancer Research Jan 2008, 28 (1A) 179-186;
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