UFT and its metabolite γ-butyrolactone (GBL) inhibit angiogenesis induced by vascular endothelial growth factor in advanced cervical carcinoma

Abstract

The aim of this study was to evaluate the potential role of UFT and its metabolite gamma-butyrolactone (GBL) for inhibition of angiogenesis induced by vascular endothelial growth factor (VEGF) in advanced cervical carcinoma by the determination of serum GBL and VEGF, and by immunohistochemical staining to assess VEGF protein expression, before and after UFT therapy. The subjects were 35 patients with an advanced cervical carcinoma and five healthy volunteers between 2002 and 2003 at Hiroshima University Hospital, under informed consent. The patients received two courses of oral fluoropyrimidine (UFT) therapy at a dose of 600 mg/day for 5 and 2 days off treatment. Serum GBL and VEGF was measured before and after UFT therapy by the gas chromatography mass spectrometry and ELISA-kit in 22 patients and five healthy volunteers, respectively. Immunohistochemical detection of VEGF protein was done in 35 cervical cancers. Results The mean serum GBL level before and after UFT therapy was 21.9 +/- 2.3 and 79.3 +/- 6.2 ng/ml, respectively, and it was significantly increased after UFT administration (P < 0.0001). The mean serum VEGF level before and after UFT therapy was 95.3 +/- 28.1 and 67.5 +/- 11.2 pg/ml, respectively, and it was decreased by UFT administration. In 20 out of 33 (66.6%) patients who were detected with VEGF protein, VEGF protein expression was decreased by UFT therapy. The Delta GBL value (GBL after UFT--GBL before UFT therapy) showed a significant inverse correlation with Delta VEGF value (VEGF after therapy--VEGF before therapy) (r2 = 0.940). Our findings suggest that UFT and its metabolite GBL inhibit angiogenesis induced by VEGF to have an antitumor effect on cervical cancer.