Cooperative stimulation of vascular endothelial growth factor expression by hypoxia and reactive oxygen species: the effect of targeting vascular endothelial growth factor and oxidative stress in an orthotopic xenograft model of bladder carcinoma.
Elevated thymidine phosphorylase has been shown to correlate with increased angiogenesis and poor prognosis in many cancers including transitional cell carcinoma of the bladder. In vitro studies have demonstrated that thymidine phosphorylase activity causes cellular oxidative stress and increases secretion of vascular endothelial growth factor. In this study, we show that thymidine phosphorylase activity also augments levels of the hypoxia-inducible factor-1alpha during in vitro hypoxia, and that thymidine phosphorylase activity and hypoxia act in concert to increase vascular endothelial growth factor (VEGF) secretion. We also demonstrate that thymidine phosphorylase overexpression confers tumorigenicity on an orthotopically implanted transitional cell carcinoma cell line. Administration of the antioxidant N-acetylcysteine together with a blocking anti-VEGF antibody abrogates the increase in tumorigenicity. Our results support the increased efficacy of combination approaches to antiangiogenic therapy.
Brown
N S
NS
Molecular Angiogenesis Group, Cancer Research UK, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Streeter
E H
EH
Jones
A
A
Harris
A L
AL
Bicknell
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002295:Carcinoma, Transitional Cell / Q000378:metabolism*; D015687:Cell Hypoxia; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D051381:Rats; D011923:Rats, Nude; D017382:Reactive Oxygen Species; D013936:Thymidine / Q000494:pharmacology; D013939:Thymidine Phosphorylase / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors / Q000096:biosynthesis* / Q000276:immunology
D000911:Antibodies, Monoclonal; D017382:Reactive Oxygen Species; D042442:Vascular Endothelial Growth Factors; D013939:Thymidine Phosphorylase; D013936:Thymidine