title: Orally administered S-1 suppresses circulating endothelial cell counts in metastatic breast cancer patients.
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.
authors.affiliation: Division of Breast Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto, Japan, w-sato@kuhp.kyoto-u.ac.jp.
authors.forename: Wakako
authors.initials: W
authors.lastname: Tsuji
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishiguro
authors.forename: Sunao
authors.initials: S
authors.lastname: Tanaka
authors.forename: Megumi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ueno
authors.forename: Masakazu
authors.initials: M
authors.lastname: Toi
mesh_terms: D015107:4-Butyrolactone / Q000097:blood; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002452:Cell Count; D018932:Chemokine CCL2 / Q000097:blood; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects*; D005260:Female; D005472:Fluorouracil / Q000097:blood; D006801:Humans; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010094:Oxonic Acid / Q000008:administration & dosage* / Q000627:therapeutic use*; D005641:Tegafur / Q000008:administration & dosage* / Q000627:therapeutic use*; D019700:Thrombospondin 1 / Q000097:blood; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D018952:Antigens, CD34; D000964:Antimetabolites, Antineoplastic; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004338:Drug Combinations; D019700:Thrombospondin 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D015107:4-Butyrolactone; D005472:Fluorouracil