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


METHODS
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).


CONCLUSIONS
Our findings suggest that UFT and its metabolite GBL inhibit angiogenesis induced by VEGF to have an antitumor effect on cervical cancer.
Nagai
Nobutaka
N
Department of Obstetrics and Gynecology, Hiroshima University Graduate School of Biological Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. n-nagai@asa-hosp.city.hiroshima.jp
Mukai
Keiji
K
Hirata
Eiji
E
Jin
Hong Hua
HH
Komatsu
Masaaki
M
Yunokawa
Mayu
M
D015107:4-Butyrolactone / Q000097:blood* / Q000494:pharmacology; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D005641:Tegafur / Q000378:metabolism / Q000494:pharmacology; D014498:Uracil / Q000378:metabolism / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000097:blood
D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D005641:Tegafur; D014498:Uracil; D015107:4-Butyrolactone