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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
9
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pubmed:dateCreated |
2000-8-3
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pubmed:abstractText |
Farnesylation of Ras is required for its transforming activity in human cancer and the reaction is catalysed by the enzyme farnesyltransferase. Recently, we discovered a novel chemical series of potent farnesyl pyrophosphate (FPP) analogues which selectively inhibited farnesyltransferase. Our most potent compound to date in this series, A-176120, selectively inhibited farnesyltransferase activity (IC(50) 1.2+/-0.3 nM) over the closely related enzymes geranylgeranyltransferase I (GGTaseI) (IC(50) 423+/-1.8 nM), geranylgeranyltransferase II (GGTaseII) (IC(50) 3000 nM) and squalene synthase (SSase) (IC(50)>10000 nM). A-176120 inhibited ras processing in H-ras-transformed NIH3T3 cells and HCT116 K-ras-mutated cells (ED(50) 1.6 and 0.5 microM, respectively). The anti-angiogenic potential of A-176120 was demonstrated by a decrease in Ras processing, cell proliferation and capillary structure formation of human umbilical vein endothelial cells (HUVEC), and a decrease in the secretion of vascular endothelial growth factor (VEGF) from HCT116 cells. In vivo, A-176120 reduced H-ras NIH3T3 tumour growth and extended the lifespan of nude mice inoculated with H- or K-ras-transformed NIH3T3 cells. A-176120 also had an additive effect in combination with cyclophosphamide in nude mice inoculated with K-ras NIH3T3 transformed cells. Overall, our results demonstrate that A-176120 is a potent FPP mimetic with both antitumour and anti-angiogenic properties.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Alkyl and Aryl Transferases,
http://linkedlifedata.com/resource/pubmed/chemical/Endothelial Growth Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Farnesyl-Diphosphate...,
http://linkedlifedata.com/resource/pubmed/chemical/Farnesyltranstransferase,
http://linkedlifedata.com/resource/pubmed/chemical/Lymphokines,
http://linkedlifedata.com/resource/pubmed/chemical/Polyisoprenyl Phosphates,
http://linkedlifedata.com/resource/pubmed/chemical/Sesquiterpenes,
http://linkedlifedata.com/resource/pubmed/chemical/Vascular Endothelial Growth Factor A,
http://linkedlifedata.com/resource/pubmed/chemical/Vascular Endothelial Growth Factors,
http://linkedlifedata.com/resource/pubmed/chemical/farnesyl pyrophosphate
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0959-8049
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pubmed:author |
pubmed-author:ArendsenD LDL,
pubmed-author:CherianS PSP,
pubmed-author:CohenJJ,
pubmed-author:DevinsWW,
pubmed-author:KovarPP,
pubmed-author:LealJJ,
pubmed-author:LeeJ YJY,
pubmed-author:NgS CSC,
pubmed-author:RosenbergSS,
pubmed-author:SaeedBB,
pubmed-author:StoutDD,
pubmed-author:TAXTT,
pubmed-author:TahirS KSK,
pubmed-author:WangY CYC,
pubmed-author:WarnerRR,
pubmed-author:ZhangH CHC
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pubmed:issnType |
Print
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pubmed:volume |
36
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1161-70
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:10854950-Alkyl and Aryl Transferases,
pubmed-meshheading:10854950-Animals,
pubmed-meshheading:10854950-Cell Division,
pubmed-meshheading:10854950-Endothelial Growth Factors,
pubmed-meshheading:10854950-Endothelium, Vascular,
pubmed-meshheading:10854950-Enzyme Inhibitors,
pubmed-meshheading:10854950-Farnesyl-Diphosphate Farnesyltransferase,
pubmed-meshheading:10854950-Farnesyltranstransferase,
pubmed-meshheading:10854950-Genes, ras,
pubmed-meshheading:10854950-Humans,
pubmed-meshheading:10854950-Lymphokines,
pubmed-meshheading:10854950-Male,
pubmed-meshheading:10854950-Mice,
pubmed-meshheading:10854950-Mice, Nude,
pubmed-meshheading:10854950-Mutation,
pubmed-meshheading:10854950-Neoplasm Transplantation,
pubmed-meshheading:10854950-Neovascularization, Pathologic,
pubmed-meshheading:10854950-Polyisoprenyl Phosphates,
pubmed-meshheading:10854950-Sesquiterpenes,
pubmed-meshheading:10854950-Transplantation, Heterologous,
pubmed-meshheading:10854950-Tumor Cells, Cultured,
pubmed-meshheading:10854950-Umbilical Veins,
pubmed-meshheading:10854950-Vascular Endothelial Growth Factor A,
pubmed-meshheading:10854950-Vascular Endothelial Growth Factors
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pubmed:year |
2000
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pubmed:articleTitle |
Inhibition of farnesyltransferase with A-176120, a novel and potent farnesyl pyrophosphate analogue.
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pubmed:affiliation |
Cancer Research, Pharmaceutical Product Research Division, Abbott Laboratories, 100 Abbott Park Road, IL 60064, Abbott Park, USA.
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pubmed:publicationType |
Journal Article
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