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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7
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pubmed:dateCreated |
1999-11-4
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pubmed:abstractText |
Oncogenic RAS alleles encode proteins that accumulate in the guanosine triphosphate (GTP)-bound state. Because post-translational processing of Ras by farnesyltransferase is essential for biologic function, inhibitors of this enzyme have been developed as rational cancer therapeutics. We have investigated farnesyltransferase inhibitor (FTI) L-744,832 in an in vivo murine model of myeloid leukemia that is associated with inactivation of the Nf1 tumor suppressor gene. Nf1 encodes a GTPase activating protein for Ras, and Nf1-deficient (Nf1-/-) hematopoietic cells show hyperactive Ras signaling through the mitogen-activated protein (MAP) kinase pathway. L-744,832 inhibited H-Ras prenylation in cell lines and in primary hematopoietic cells and abrogated the in vitro growth of myeloid progenitor colonies in response to granulocyte-macrophage colony-stimulating factor (GM-CSF). This FTI also partially blocked GM-CSF-induced MAP kinase activation, but did not reduce constitutively elevated levels of MAP kinase activity in primary Nf1-/- cells. Injection of a single dose of 40 or 80 mg/kg of L-744, 832 increased the amount of unprocessed H-Ras in bone marrow cells, but had no detectable effect on N-Ras. Adoptive transfer of Nf1-/- hematopoietic cells into irradiated mice induces a myeloproliferative disorder that did not respond to L-744,832 treatment. We speculate that the lack of efficacy in this model is due to the resistance of N-Ras and K-Ras processing to inhibition by this FTI.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
0006-4971
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
94
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2469-76
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:10498620-Alkyl and Aryl Transferases,
pubmed-meshheading:10498620-Animals,
pubmed-meshheading:10498620-Antineoplastic Agents,
pubmed-meshheading:10498620-Cell Division,
pubmed-meshheading:10498620-Cells, Cultured,
pubmed-meshheading:10498620-Colony-Forming Units Assay,
pubmed-meshheading:10498620-Crosses, Genetic,
pubmed-meshheading:10498620-Farnesyltranstransferase,
pubmed-meshheading:10498620-Female,
pubmed-meshheading:10498620-Genes, Tumor Suppressor,
pubmed-meshheading:10498620-Granulocyte-Macrophage Colony-Stimulating Factor,
pubmed-meshheading:10498620-Hematopoietic Stem Cells,
pubmed-meshheading:10498620-Leukemia, Myeloid,
pubmed-meshheading:10498620-Leukocyte Count,
pubmed-meshheading:10498620-Liver,
pubmed-meshheading:10498620-Male,
pubmed-meshheading:10498620-Methionine,
pubmed-meshheading:10498620-Mice,
pubmed-meshheading:10498620-Mice, Inbred C57BL,
pubmed-meshheading:10498620-Mice, Inbred Strains,
pubmed-meshheading:10498620-Mice, Knockout,
pubmed-meshheading:10498620-Neurofibromin 1,
pubmed-meshheading:10498620-Protein Prenylation,
pubmed-meshheading:10498620-Proteins,
pubmed-meshheading:10498620-ras Proteins
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pubmed:year |
1999
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pubmed:articleTitle |
In vitro and in vivo effects of a farnesyltransferase inhibitor on Nf1-deficient hematopoietic cells.
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pubmed:affiliation |
Department of Pediatrics, University of California, San Francisco, CA, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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