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Erschienen in: International Journal of Clinical Oncology 3/2014

01.06.2014 | Original Article

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

verfasst von: Wakako Tsuji, Hiroshi Ishiguro, Sunao Tanaka, Megumi Takeuchi, Takayuki Ueno, Masakazu Toi

Erschienen in: International Journal of Clinical Oncology | Ausgabe 3/2014

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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.
Literatur
1.
Zurück zum Zitat 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 63:4342–4346PubMed 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 63:4342–4346PubMed
2.
Zurück zum Zitat 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 69:763–772PubMed 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 69:763–772PubMed
3.
Zurück zum Zitat Milano G, Ferrero JM, Francois E (2004) Comparative pharmacology of oral fluoropyrimidines: a focus on pharmacokinetics, pharmacodynamics and pharmacomodulation. Br J Cancer 91:613–617PubMedCentralPubMed Milano G, Ferrero JM, Francois E (2004) Comparative pharmacology of oral fluoropyrimidines: a focus on pharmacokinetics, pharmacodynamics and pharmacomodulation. Br J Cancer 91:613–617PubMedCentralPubMed
4.
Zurück zum Zitat 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 27:1368–1374PubMedCrossRef 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 27:1368–1374PubMedCrossRef
5.
Zurück zum Zitat 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 119:633–641PubMedCrossRef 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 119:633–641PubMedCrossRef
6.
Zurück zum Zitat 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 100:14–20PubMedCrossRef 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 100:14–20PubMedCrossRef
7.
Zurück zum Zitat Hayes DF, Thor AD, Dressler LG et al (2007) HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 357:1496–1506PubMedCrossRef Hayes DF, Thor AD, Dressler LG et al (2007) HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 357:1496–1506PubMedCrossRef
8.
Zurück zum Zitat Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4:423–436PubMedCrossRef Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4:423–436PubMedCrossRef
9.
Zurück zum Zitat 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 66:3386–3391PubMedCrossRef 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 66:3386–3391PubMedCrossRef
10.
Zurück zum Zitat Browder T, Butterfield CE, Kraling BM et al (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886PubMed Browder T, Butterfield CE, Kraling BM et al (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886PubMed
11.
Zurück zum Zitat 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 4:163–173PubMedCrossRef 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 4:163–173PubMedCrossRef
12.
Zurück zum Zitat 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 5:2185–2191PubMed 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 5:2185–2191PubMed
13.
Zurück zum Zitat Asahara T, Murohara T, Sullivan A et al (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967PubMedCrossRef Asahara T, Murohara T, Sullivan A et al (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967PubMedCrossRef
14.
Zurück zum Zitat Bertolini F, Mancuso P, Shaked Y et al (2007) Molecular and cellular biomarkers for angiogenesis in clinical oncology. Drug Discov Today 12:806–812PubMedCrossRef Bertolini F, Mancuso P, Shaked Y et al (2007) Molecular and cellular biomarkers for angiogenesis in clinical oncology. Drug Discov Today 12:806–812PubMedCrossRef
15.
Zurück zum Zitat 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 94:524–531PubMedCentralPubMedCrossRef 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 94:524–531PubMedCentralPubMedCrossRef
16.
Zurück zum Zitat 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 107:133–138PubMedCrossRef 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 107:133–138PubMedCrossRef
17.
Zurück zum Zitat Shaked Y, Emmenegger U, Man S et al (2005) Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 106:3058–3061PubMedCentralPubMedCrossRef Shaked Y, Emmenegger U, Man S et al (2005) Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 106:3058–3061PubMedCentralPubMedCrossRef
18.
Zurück zum Zitat 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 25:214–221PubMedCrossRef 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 25:214–221PubMedCrossRef
19.
Zurück zum Zitat Bertolini F, Shaked Y, Mancuso P et al (2006) The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer 6:835–845PubMedCrossRef Bertolini F, Shaked Y, Mancuso P et al (2006) The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer 6:835–845PubMedCrossRef
20.
Zurück zum Zitat 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 108:452–459PubMedCentralPubMedCrossRef 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 108:452–459PubMedCentralPubMedCrossRef
21.
Zurück zum Zitat 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 98:1312–1319PubMedCentralPubMedCrossRef 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 98:1312–1319PubMedCentralPubMedCrossRef
22.
Zurück zum Zitat 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 6:3282–3289PubMed 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 6:3282–3289PubMed
23.
Zurück zum Zitat 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 785:73–80PubMedCrossRef 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 785:73–80PubMedCrossRef
24.
Zurück zum Zitat Cristofanilli M, Budd GT, Ellis MJ et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781–791PubMedCrossRef Cristofanilli M, Budd GT, Ellis MJ et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781–791PubMedCrossRef
25.
26.
Zurück zum Zitat 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 13:3198–3206CrossRef 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 13:3198–3206CrossRef
27.
Zurück zum Zitat 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 98:418–424PubMed 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 98:418–424PubMed
28.
Zurück zum Zitat Kramer G, Schwarz S, Hagg M et al (2006) Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles. Br J Cancer 94:1592–1598PubMedCentralPubMed Kramer G, Schwarz S, Hagg M et al (2006) Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles. Br J Cancer 94:1592–1598PubMedCentralPubMed
29.
Zurück zum Zitat 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 56:399–404PubMedCrossRef 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 56:399–404PubMedCrossRef
30.
Zurück zum Zitat Asahara T, Takahashi T, Masuda H et al (1999) VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 18:3964–3972PubMedCentralPubMedCrossRef Asahara T, Takahashi T, Masuda H et al (1999) VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 18:3964–3972PubMedCentralPubMedCrossRef
31.
Zurück zum Zitat 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 47:2265–2272PubMedCrossRef 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 47:2265–2272PubMedCrossRef
Metadaten
Titel
Orally administered S-1 suppresses circulating endothelial cell counts in metastatic breast cancer patients
verfasst von
Wakako Tsuji
Hiroshi Ishiguro
Sunao Tanaka
Megumi Takeuchi
Takayuki Ueno
Masakazu Toi
Publikationsdatum
01.06.2014
Verlag
Springer Japan
Erschienen in
International Journal of Clinical Oncology / Ausgabe 3/2014
Print ISSN: 1341-9625
Elektronische ISSN: 1437-7772
DOI
https://doi.org/10.1007/s10147-013-0570-5

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