title: Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis.
abstract: Angiogenesis is a prerequisite for tumour progression and is highly regulated by growth factors and cytokines a number of which also stimulate the production of nitric oxide. Asymmetric dimethylarginine is an endogenous inhibitor of nitric oxide synthesis. Asymmetric dimethylarginine is metabolised by dimethylarginine dimethylaminohydrolase. To study the effect of dimethylarginine dimethylaminohydrolase on tumour growth and vascular development, the rat C6 glioma cell line was manipulated to overexpress the rat gene for dimethylarginine dimethylaminohydrolase I. Enhanced expression of dimethylarginine dimethylaminohydrolase I increased nitric oxide synthesis (as indicated by a two-fold increase in the production of cGMP), expression and secretion of vascular endothelial cell growth factor, and induced angiogenesis in vitro. Tumours derived from these cells grew more rapidly in vivo than cells with normal dimethylarginine dimethylaminohydrolase I expression. Immunohistochemical and magnetic resonance imaging measurements were consistent with increased tumour vascular development. Furthermore, dimethylarginine dimethylaminohydrolase activity was detected in a series of human tumours. This data demonstrates that dimethylarginine dimethylaminohydrolase plays a pivotal role in tumour growth and the development of the tumour vasculature by regulating the concentration of nitric oxide and altering vascular endothelial cell growth factor production.
authors.affiliation: Department of Biochemistry and Immunology, St George's Hospital Medical School, London SW17 0RE, UK.
authors.forename: V
authors.initials: V
authors.lastname: Kostourou
authors.forename: S P
authors.initials: SP
authors.lastname: Robinson
authors.forename: J E
authors.initials: JE
authors.lastname: Cartwright
authors.forename: G St J
authors.initials: GS
authors.lastname: Whitley
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001254:Astrocytoma / Q000378:metabolism / Q000473:pathology; D015152:Blotting, Northern; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D017931:DNA Primers; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D009569:Nitric Oxide; D000581:Amidohydrolases; C059999:dimethylargininase; D006152:Cyclic GMP