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10.1245/s10434-008-9963-5
Annals of Surgical Oncology 15:2301-2309 (2008)
© 2008 Society of Surgical Oncology
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Original Article

Effects of Combined Administration of DPD-Inhibitory Oral Fluoropyrimidine, S-1, Plus Paclitaxel on Gene Expressions of Fluoropyrimidine Metabolism-Related Enzymes in Human Gastric Xenografts

Yoichi Sakurai, MD, PhD, FACS1, Ikuo Yoshida, MD1, Shingo Kamoshida, PhD2, Kazuki Inaba, MD1, Jun Isogaki, MD1, Yoshiyuki Komori, MD1, Ichiro Uyama, MD, FACS1 and Yutaka Tsutsumi, MD3

1 Department of Surgery, Fujita Health University School of Medicine, 1-98 Dengakugakubo Kutsukake-cho, Toyoake, Aichi 470-1192, Japan
2 Laboratory of Pathology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Hyogo 654-0142, Japan
3 Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan

Correspondence: Address correspondence and reprint requests to: Yoichi Sakurai, MD, PhD, FACS; E-mail: ysakurai{at}fujita-hu.ac.jp

Background: S-1 is the most effective oral fluoropyrimidine derivative widely used for patients with gastric carcinoma in Japan. Although S-1 plus taxane has been a promising candidate as an effective chemotherapeutic regimen, the mechanisms of its additive or synergistic anticancer effects and changes in gene expression after the administration of these agents have not yet been fully elucidated.

Methods: Experimental chemotherapy was performed using human gastric carcinoma xenografts, MKN-45 and TMK-1, to examine anticancer effects and gene expressions of fluoropyrimidine metabolism-related enzymes including thymidine phosphorylase (TP), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribo-syltransferase (OPRT), and uridine phosphorylase (UP). Nude mice were treated with S-1, paclitaxel, and their combination. After treatment, in vivo antitumor effects of S-1, paclitaxel alone, and their combination and the effects on gene expressions of enzymes involved in 5-fluorouracil metabolism were examined using the RT-PCR method.

Results: The combined use of S-1 and paclitaxel showed additive to synergistic antitumor effects on both gastric cancer xenografts. While consistent upregulation of dThPase and DPD gene expression was exhibited after administration of S-1, no further increase of dThPase gene expression after combined use of S-1 with paclitaxel was observed. There was no increase in TS gene expression after the administration of either S-1 alone or paclitaxel alone.

Conclusion: These results provide some insight into the mechanism and/or rationale underlying the additive to synergistic effect of combined administration of S-1 and paclitaxel in gastric carcinoma.

Key Words: 5-fluorouracil • Cisplatin • Nude mice • Gastric cancer • Thymidylate synthase • Dihydropyrimidine dehydrogenase






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