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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

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Abstract

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 phosphoribosyltransferase (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.

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References

  1. Macdonald JS, Gohmann JJ. Chemotherapy of advanced gastric cancer: present status, future prospects. Semin Oncol 1988; 15:42–9.

    PubMed  CAS  Google Scholar 

  2. Maehara Y. S-1 in gastric cancer: a comprehensive review. Gastric Cancer 2004; 6 Suppl 1:2–8.

    Google Scholar 

  3. Shirasaka T, Shimamato Y, Ohshimo H, et al. 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 1996; 7:548–57.

    Article  PubMed  CAS  Google Scholar 

  4. Shirasaka T, Nakano K, Takechi T, et al. Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res 1996; 56:2602–6.

    PubMed  CAS  Google Scholar 

  5. Schoffski P. The modulated oral fluoropyrimidine prodrug S-1, and its use in gastrointestinal cancer and other solid tumors. Anticancer Drugs 2004; 15:85–106.

    Article  PubMed  Google Scholar 

  6. Sugimachi K, Maehara Y, Horikoshi N, et al. An early phase II study of oral S-1, a newly developed 5-fluorouracil derivative for advanced and recurrent gastrointestinal cancers. The S-1 Gastrointestinal Cancer Study Group. Oncology 1999; 57:202–10.

    Article  PubMed  CAS  Google Scholar 

  7. Sakata Y, Ohtsu A, Horikoshi N, et al. 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 1998; 34:1715–20.

    Article  PubMed  CAS  Google Scholar 

  8. Koizumi W, Kurihara M, Nakano S, et al. Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. For the S-1 Cooperative Gastric Cancer Study Group. Oncology 2000; 58:191–7.

    Article  PubMed  CAS  Google Scholar 

  9. Wils JA, Klein HO, Wagener DJ, et al. Sequential high-dose methotrexate and fluorouracil combined with doxorubicin—a step ahead in the treatment of advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group. J Clin Oncol 1991; 9:827–31.

    PubMed  CAS  Google Scholar 

  10. Kelsen D, Atiq OT, Saltz L, et al. FAMTX versus etoposide, doxorubicin, and cisplatin: a random assignment trial in gastric cancer. J Clin Oncol 1992; 10:541–8.

    PubMed  CAS  Google Scholar 

  11. Kim NK, Park YS, Heo DS, et al. A phase III randomized study of 5-fluorouracil and cisplatin versus 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil alone in the treatment of advanced gastric cancer. Cancer 1993; 71:3813–8.

    Article  PubMed  CAS  Google Scholar 

  12. Webb A, Cunningham D, Scarffe JH, et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 1997; 15:261–7.

    PubMed  CAS  Google Scholar 

  13. Iwase H, Shimada M, Tsuzuki T, et al. A phase I study of S-1 administration and a 24-h infusion of cisplatin plus paclitaxel in patients with advanced gastric cancer. Anticancer Res 2006; 26:1605–9.

    PubMed  CAS  Google Scholar 

  14. Kondo K, Kobayashi M, Kojima H, et al. Phase I evaluation of continuous 5-fluorouracil infusion followed by weekly paclitaxel in patients with advanced or recurrent gastric cancer. Jpn J Clin Oncol 2005; 35:332–7.

    Article  PubMed  Google Scholar 

  15. Kano Y, Akutsu M, Tsunoda S, et al. Schedule-dependent interaction between paclitaxel and 5-fluorouracil in human carcinoma cell lines in vitro. Br J Cancer 1996; 74:704–10.

    PubMed  CAS  Google Scholar 

  16. Fujitani K, Narahara H, Takiuchi H, et al. Phase I and pharmacokinetic study of S-1 combined with weekly paclitaxel in patients with advanced gastric cancer. Oncology 2005; 69:414–20.

    Article  PubMed  CAS  Google Scholar 

  17. Ueda Y, Yamagishi H, Ichikawa D, et al. Phase I study of a combination of S-1 and weekly paclitaxel in patients with advanced or recurrent gastric cancer. Oncology 2005; 69:261–8.

    Article  PubMed  CAS  Google Scholar 

  18. Sawada N, Nose T, Ishikawa T, et al. Enhancement of antitumor activity of 5′-deoxy-5-fluorouridine (Furtulon) by taxane in human gastric cancer xenografts. Oncol Rep 2005; 14:53–7.

    PubMed  CAS  Google Scholar 

  19. Yoshida K, Ninomiya M, Takakura N, et al. Phase II study of docetaxel and S-1 combination therapy for advanced or recurrent gastric cancer. Clin Cancer Res 2006; 12:3402–7.

    Article  PubMed  CAS  Google Scholar 

  20. Sakurai Y, Yoshida I, Tonomura S, et al. Weekly administration of paclitaxel attenuated rectal stenosis caused by multiple peritoneal recurrence 8 years after the resection of gastric carcinoma. Gastric Cancer 2003; 6:243–9.

    Article  PubMed  Google Scholar 

  21. Hironaka S, Zenda S, Boku N, et al. Weekly paclitaxel as second-line chemotherapy for advanced or recurrent gastric cancer. Gastric Cancer 2006; 9:14–8.

    Article  PubMed  CAS  Google Scholar 

  22. Ohtsu A, Boku N, Tamura F, et al. An early phase II study of a 3-hour infusion of paclitaxel for advanced gastric cancer. Am J Clin Oncol 1998; 21:416–9.

    Article  PubMed  CAS  Google Scholar 

  23. Yamada Y, Shirao K, Ohtsu A, et al. Phase II trial of paclitaxel by three-hour infusion for advanced gastric cancer with short premedication for prophylaxis against paclitaxel-associated hypersensitivity reactions. Ann Oncol 2003; 12:1133–7.

    Article  Google Scholar 

  24. Yamaguchi K, Tada M, Horikoshi N, et al. Phase II study of paclitaxel with 3-h infusion in patients with advanced gastric cancer. Gastric Cancer 2002; 5:90–5.

    Article  PubMed  CAS  Google Scholar 

  25. Mochiki E, Ohno T, Kamiyama Y, et al. Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer. Br J Cancer 2006; 95:1642–7.

    Article  PubMed  CAS  Google Scholar 

  26. Hokita S, Aikou T, Miyazono F, et al. A phase I combination chemotherapy study of biweekly paclitaxel and S-1 administration in patients with advanced gastric cancer. Cancer Chemother Pharmacol 2006; 57:736–40.

    Article  PubMed  CAS  Google Scholar 

  27. Yamaguchi K, Shimamura T, Hyodo I, et al. Phase I/II study of docetaxel and S-1 in patients with advanced gastric cancer. Br J Cancer 2006; 94:1803–8.

    Article  PubMed  CAS  Google Scholar 

  28. Motoyama T, Hojo H, Watanabe H. Comparison of seven cell lines derived from human gastric carcinomas. Acta Pathol Jpn 1986; 36:65–83.

    PubMed  CAS  Google Scholar 

  29. Ochiai A, Yasui W, Tahara E. Growth-promoting effect of gastrin on human gastric carcinoma cell line TMK-1. Jpn J Cancer Res 1985; 76:1064–71.

    PubMed  CAS  Google Scholar 

  30. Yamada Y, Yoshida T, Hayashi K, et al. p53 gene mutations in gastric cancer metastases and in gastric cancer cell lines derived from metastases. Cancer Res 1991; 51:5800–5.

    PubMed  CAS  Google Scholar 

  31. Geran RI, Greenberg NH, Schumacher AM, et al. Protocols for screening chemical agents and natural products against animal tumors and other biological systems. 3rd ed. Cancer Chemother Rep 1972; 3:51–61.

    Google Scholar 

  32. Ovejera AA, Houchens DP, Barker AD. Chemotherapy of human tumor xenografts in genetically athymic mice. Ann Clin Lab Sci 1978; 8:50–6.

    PubMed  CAS  Google Scholar 

  33. Houchens DP, Ovejera AA, Baker A. (2007) The therapy of human tumors in athymic (nude) mice. In: Houchens DP, Ovejera AA (eds). Proceedings of the Symposium on the Use of Athymic (nude) Mice in Cancer Research. Gustav Fisher, New York, Stuttgart, pp 267–80

  34. Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 1992; 119:493–501.

    Article  PubMed  CAS  Google Scholar 

  35. Leers MP, Kolgen W, Bjorklund V, et al. Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed during early apoptosis. J Pathol 1999; 187:567–72.

    Article  PubMed  CAS  Google Scholar 

  36. Sawada N, Ishikawa T, Sekiguchi F, et al. X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts. Clin Cancer Res 1999; 5:2948–53.

    PubMed  CAS  Google Scholar 

  37. Eda H, Fujimoto K, Watanabe S, et al. Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5′-deoxy-5-fluorouridine. Cancer Chemother Pharmacol 1993; 32:333–8.

    Article  PubMed  CAS  Google Scholar 

  38. Fukushima M, Okabe H, Takechi T, et al. Induction of thymidine phosphorylase by interferon and taxanes occurs only in human cancer cells with low thymidine phosphorylase activity. Cancer Lett 2002; 187:103–10.

    Article  PubMed  CAS  Google Scholar 

  39. Sawada N, Ishikawa T, Fukase Y, et al. Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 1998; 4:1013–9.

    PubMed  CAS  Google Scholar 

  40. Sakurai Y, Uraguchi T, Imazu H, et al. Changes in thymidylate synthase and its inhibition rate and changes in dihydropyrimidine dehydrogenase after the administration of 5-fluorouracil with cisplatin to nude mice with gastric cancer xenograft SC-1-NU. Gastric Cancer 2004; 7:110–6.

    Article  PubMed  CAS  Google Scholar 

  41. Omura K, Kawakami K, Kanehira E, et al. The number of 5-fluoro-2′-deoxyuridine-5′-monophosphate binding sites and reduced folate pool in human colorectal carcinoma tissues: changes after tegafur and uracil treatment. Cancer Res 1995; 55:3897–901.

    PubMed  CAS  Google Scholar 

  42. Langenbach RJ, Danenberg PV, Heidelberger C. Thymidylate synthetase: mechanism of inhibition by 5-fluoro-2′-deoxyuridylate. Biochem Biophys Res Commun 1972; 48:1565–71.

    Article  PubMed  CAS  Google Scholar 

  43. Santi DV, McHenry CS. 5-Fluoro-2′-deoxyuridylate: covalent complex with thymidylate synthetase. Proc Natl Acad Sci USA 1972; 69:1855–7.

    Article  PubMed  CAS  Google Scholar 

  44. Spears CP, Shahinian AH, Moran RG, et al. In vivo kinetics of thymidylate synthetase inhibition of 5-fluorouracil-sensitive and -resistant murine colon adenocarcinomas. Cancer Res 1982; 42:450–6.

    PubMed  CAS  Google Scholar 

  45. Parker WB, Cheng YC. Metabolism and mechanism of action of 5-fluorouracil. Pharmacol Ther 1990; 48:381–95.

    Article  PubMed  CAS  Google Scholar 

  46. Johnston PG, Lenz HJ, Leichman CG, et al. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res 1995; 55:1407–12.

    PubMed  CAS  Google Scholar 

  47. Salonga D, Danenberg KD, Johnson M, et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 2000; 6:1322–7.

    PubMed  CAS  Google Scholar 

  48. Sakurai Y, Sakamoto K, Sugimoto Y, et al. Orotate phosphoribosyltransferase levels measured by a newly established enzyme-linked immunosorbent assay in gastric carcinoma. Cancer Sci 2006; 97:492–8.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This study was supported in part by grants from Ministry of Health, Labor and Welfare (#14571242) and from Fujita Health University. The authors thank Miss Akemi Someya for an excellent technical assistance for performing the animal experiments.

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Authors and Affiliations

  1. Department of Surgery, Fujita Health University School of Medicine, 1-98 Dengakugakubo Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan

    Yoichi Sakurai MD, PhD, FACS, Ikuo Yoshida MD, Kazuki Inaba MD, Jun Isogaki MD, Yoshiyuki Komori MD & Ichiro Uyama MD, FACS

  2. Laboratory of Pathology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Hyogo, 654-0142, Japan

    Shingo Kamoshida PhD

  3. Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan

    Yutaka Tsutsumi MD

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  1. Yoichi Sakurai MD, PhD, FACS
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Correspondence to Yoichi Sakurai MD, PhD, FACS.

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Sakurai, Y., Yoshida, I., Kamoshida, S. et al. 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. Ann Surg Oncol 15, 2301–2309 (2008). https://doi.org/10.1245/s10434-008-9963-5

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  • DOI: https://doi.org/10.1245/s10434-008-9963-5

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