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

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. 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(A (R)) 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. A total of 18 patients were enrolled. The plasma GBL levels on days 15 and 57 were 41.3 +/- A 15.8 and 41.0 +/- A 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. 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.