Skip to main content

Advertisement

SpringerLink
Log in

Orally administered S-1 suppresses circulating endothelial cell counts in metastatic breast cancer patients

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

S-1 is an oral cytotoxic preparation that contains tegafur. Gamma-butyrolactone (GBL) is a metabolite of tegafur that is known to suppress vascular endothelial growth factor (VEGF)-mediated angiogenic activity. The aim of this study was to determine the change in circulating endothelial cell (CEC) counts, GBL levels, and angiogenesis-related factors during S-1 administration in metastatic breast cancer (MBC) patients.

Methods

Patients with HER2-negative MBC were eligible. S-1 was administered orally twice daily in a 4 week on/2 week off cycle until disease progression or unacceptable toxicity occurred. Blood was collected on the following: days 1, 43, 85 (before each cycle of S-1 administration), days 15, 57 (1 h after S-1 administration), and day 29. The CellSearch® system was used to count the CECs. The gas chromatographic–mass spectrometric method was used to measure plasma GBL and 5-FU levels. Levels of VEGF were assayed by enzyme-linked immunosorbent assay.

Results

A total of 18 patients were enrolled. The plasma GBL levels on days 15 and 57 were 41.3 ± 15.8 and 41.0 ± 11.2 ng/mL, respectively. The CEC levels decreased on day 15, and significantly low levels were maintained until day 85 (P = 0.002 vs day 1). The plasma VEGF levels significantly decreased on day 15 (P = 0.012 vs day 1) and had a tendency to decrease until day 57.

Conclusions

This exploratory study showed that GBL levels increased, VEGF levels decreased, and CEC levels were suppressed during S-1 administration. S-1 appears to have anti-angiogenic activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Bertolini F, Paul S, Mancuso P et al (2003) Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 63:4342–4346

    CAS  PubMed  Google Scholar 

  2. Fujii S, Ikenaka K, Fukushima M et al (1978) Effect of uracil and its derivatives on antitumor activity of 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil. Gann 69:763–772

    PubMed  Google Scholar 

  3. Milano G, Ferrero JM, Francois E (2004) Comparative pharmacology of oral fluoropyrimidines: a focus on pharmacokinetics, pharmacodynamics and pharmacomodulation. Br J Cancer 91:613–617

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Watanabe T, Sano M, Takashima S et al (2009) Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial. J Clin Oncol 27:1368–1374

    Article  CAS  PubMed  Google Scholar 

  5. Ohashi Y, Watanabe T, Sano M et al (2010) Efficacy of oral tegafur-uracil (UFT) as adjuvant therapy as compared with classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in early breast cancer: a pooled analysis of two randomized controlled trials (N.SAS-BC 01 trial and CUBC trial). Breast Cancer Res Treat 119:633–641

    Article  CAS  PubMed  Google Scholar 

  6. Gennari A, Sormani MP, Pronzato P et al (2008) HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 100:14–20

    Article  CAS  PubMed  Google Scholar 

  7. Hayes DF, Thor AD, Dressler LG et al (2007) HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 357:1496–1506

    Article  CAS  PubMed  Google Scholar 

  8. Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4:423–436

    Article  CAS  PubMed  Google Scholar 

  9. Munoz R, Man S, Shaked Y et al (2006) Highly efficacious nontoxic preclinical treatment for advanced metastatic breast cancer using combination oral UFT-cyclophosphamide metronomic chemotherapy. Cancer Res 66:3386–3391

    Article  CAS  PubMed  Google Scholar 

  10. Browder T, Butterfield CE, Kraling BM et al (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886

    CAS  PubMed  Google Scholar 

  11. Basaki Y, Chikahisa L, Aoyagi K et al (2001) gamma-Hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor. Angiogenesis 4:163–173

    Article  CAS  PubMed  Google Scholar 

  12. Yonekura K, Basaki Y, Chikahisa L et al (1999) UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice. Clin Cancer Res 5:2185–2191

    CAS  PubMed  Google Scholar 

  13. Asahara T, Murohara T, Sullivan A et al (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967

    Article  CAS  PubMed  Google Scholar 

  14. Bertolini F, Mancuso P, Shaked Y et al (2007) Molecular and cellular biomarkers for angiogenesis in clinical oncology. Drug Discov Today 12:806–812

    Article  CAS  PubMed  Google Scholar 

  15. Furstenberger G, von Moos R, Lucas R et al (2006) Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer. Br J Cancer 94:524–531

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Naik RP, Jin D, Chuang E et al (2008) Circulating endothelial progenitor cells correlate to stage in patients with invasive breast cancer. Breast Cancer Res Treat 107:133–138

    Article  PubMed  Google Scholar 

  17. Shaked Y, Emmenegger U, Man S et al (2005) Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 106:3058–3061

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Nagai N, Mukai K, Hirata E et al (2008) UFT and its metabolite gamma-butyrolactone (GBL) inhibit angiogenesis induced by vascular endothelial growth factor in advanced cervical carcinoma. Med Oncol 25:214–221

    Article  CAS  PubMed  Google Scholar 

  19. Bertolini F, Shaked Y, Mancuso P et al (2006) The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer 6:835–845

    Article  CAS  PubMed  Google Scholar 

  20. Mancuso P, Colleoni M, Calleri A et al (2006) Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood 108:452–459

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Allegrini G, Falcone A, Fioravanti A et al (2008) A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients. Br J Cancer 98:1312–1319

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Ueno T, Toi M, Saji H et al (2000) Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin Cancer Res 6:3282–3289

    CAS  PubMed  Google Scholar 

  23. Fukui Y, Matsusima E, Muramoto K et al (2003) Validation of a simple gas chromatographic–mass spectrometric method for the determination of gamma-butyrolactone in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 785:73–80

    Article  CAS  PubMed  Google Scholar 

  24. Cristofanilli M, Budd GT, Ellis MJ et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781–791

    Article  CAS  PubMed  Google Scholar 

  25. Cummings J, Ward TH, Greystoke A et al (2008) Biomarker method validation in anticancer drug development. Br J Pharmacol 153:646–656

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Olofsson MH, Ueno T, Pan Y et al (2007) Cytokeratin-18 is a useful serum biomarker for early determination of response of breast carcinomas to chemotherapy. Clin Cancer Res : Off J Am Assoc Cancer Res 13:3198–3206

    Article  CAS  Google Scholar 

  27. Emi Y, Sumiyoshi Y, Oki E et al (2007) Pharmacokinetics of gamma-hydroxybutylic acid (GHB) and gamma-butyrolactone (GBL), the anti-angiogenic metabolites of oral fluoropyrimidine UFT, in patients with gastric cancer. Fukuoka Igaku Zasshi 98:418–424

    CAS  PubMed  Google Scholar 

  28. Kramer G, Schwarz S, Hagg M et al (2006) Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles. Br J Cancer 94:1592–1598

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Ulukaya E, Yilmaztepe A, Akgoz S et al (2007) The levels of caspase-cleaved cytokeratin 18 are elevated in serum from patients with lung cancer and helpful to predict the survival. Lung Cancer 56:399–404

    Article  PubMed  Google Scholar 

  30. Asahara T, Takahashi T, Masuda H et al (1999) VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 18:3964–3972

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Ali AM, Ueno T, Tanaka S et al (2011) Determining circulating endothelial cells using CellSearch system during preoperative systemic chemotherapy in breast cancer patients. Eur J Cancer 47:2265–2272

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We express our gratitude to the patients who participated in this exploratory trial. We thank Dr. Yasufumi Teramura (Hikone Municipal Hospital, Shiga), Dr. Satoru Nishimura, and Dr. Yasuo Matsutani (Tenri Hospital, Nara) for providing data support. We also thank Ms. Masako Ishida for her excellent clinical research assistance. We appreciate Dr. Teiji Takechi (Taiho Pharmaceutical Co. Ltd., Tokyo) for his critical review of the manuscript. This study was supported by Taiho Pharmaceutical Co. Ltd.

Conflict of interest

Wakako Tsuji was an employee of Kyoto University’s Sponsored Research Program funded by Taiho Pharmaceutical Co., Ltd.; Masakazu Toi received honoraria and research funding from Taiho Pharmaceutical Co., Ltd.; Hiroshi Ishiguro received honoraria and research funding from Taiho Pharmaceutical Co., Ltd.; Takayuki Ueno, Sunao Tanaka, and Megumi Takeuchi have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Breast Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto, Japan

    Wakako Tsuji, Sunao Tanaka, Megumi Takeuchi, Takayuki Ueno & Masakazu Toi

  2. Outpatient Oncology Unit, Kyoto University Hospital, Kyoto, Japan

    Hiroshi Ishiguro

Authors
  1. Wakako Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Ishiguro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sunao Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Megumi Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takayuki Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masakazu Toi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wakako Tsuji.

About this article

Cite this article

Tsuji, W., Ishiguro, H., Tanaka, S. et al. Orally administered S-1 suppresses circulating endothelial cell counts in metastatic breast cancer patients. Int J Clin Oncol 19, 452–459 (2014). https://doi.org/10.1007/s10147-013-0570-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-013-0570-5

Keywords

Search

Navigation