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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
8
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pubmed:dateCreated |
2005-10-5
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pubmed:abstractText |
The majority of patients with systemic mast cell disease express the imatinib-resistant Asp816Val (D816V) mutation in the KIT receptor tyrosine kinase. Limited treatment options exist for aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL). We evaluated whether PKC412, a small-molecule inhibitor of KIT with a different chemical structure from imatinib, may have therapeutic use in advanced SM with the D816V KIT mutation. We treated a patient with MCL (with an associated myelodysplastic syndrome (MDS)/myeloproliferative disorder [MPD]) based on in vitro studies demonstrating that PKC412 could inhibit D816V KIT-transformed Ba/F3 cell growth with a 50% inhibitory concentration (IC50) of 30 nM to 40 nM. The patient exhibited a partial response with significant resolution of liver function abnormalities. In addition, PKC412 treatment resulted in a significant decline in the percentage of peripheral blood mast cells and serum histamine level and was associated with a decrease in KIT phosphorylation and D816V KIT mutation frequency. The patient died after 3 months of therapy due to progression of her MDS/MPD to acute myeloid leukemia (AML). This case indicates that KIT tyrosine kinase inhibition is a feasible approach in SM, but single-agent clinical efficacy may be limited by clonal evolution in the advanced leukemic phase of this disease.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-11230495,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-11369651,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-11786393,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-11861291,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-12124173,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-12148892,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-12472593,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-12681363,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-12781364,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-12879016,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-12901973,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-12930381,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-12932387,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-12933573,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-14551138,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-15251969,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-15345597,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-15448205,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-15790786,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-16163256,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-7479840,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-7508174,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-7691885,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15972446-8589724
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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 |
pubmed-author:ArberDaniel ADA,
pubmed-author:BerubéCarolineC,
pubmed-author:ChenChing-ChengCC,
pubmed-author:CohenPamela SPS,
pubmed-author:CoutréSteven ESE,
pubmed-author:DurocherJeffrey AJA,
pubmed-author:GalliStephen JSJ,
pubmed-author:GeorgeTracy ITI,
pubmed-author:GillilandD GaryDG,
pubmed-author:GotlibJasonJ,
pubmed-author:GrowneyJoseph DJD,
pubmed-author:HeinrichMichael CMC,
pubmed-author:KajiguchiTomohiroT,
pubmed-author:LichyJack HJH,
pubmed-author:LillebergStan LSL,
pubmed-author:NeckersLenL,
pubmed-author:RuanJiaJ,
pubmed-author:WangYanfengY,
pubmed-author:WilliamsChristopherC
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
106
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2865-70
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:15972446-Aspartic Acid,
pubmed-meshheading:15972446-Cell Proliferation,
pubmed-meshheading:15972446-Cells, Cultured,
pubmed-meshheading:15972446-Female,
pubmed-meshheading:15972446-Humans,
pubmed-meshheading:15972446-Immunophenotyping,
pubmed-meshheading:15972446-Leukemia, Mast-Cell,
pubmed-meshheading:15972446-Middle Aged,
pubmed-meshheading:15972446-Mutation,
pubmed-meshheading:15972446-Phosphorylation,
pubmed-meshheading:15972446-Protein Kinase Inhibitors,
pubmed-meshheading:15972446-Protein-Tyrosine Kinases,
pubmed-meshheading:15972446-Proto-Oncogene Proteins c-kit,
pubmed-meshheading:15972446-Staurosporine
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pubmed:year |
2005
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pubmed:articleTitle |
Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation.
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pubmed:affiliation |
Department of Medicine, Division of Hematology, Stanford University, Stanford Cancer Center, 875 Blake Wilbur Dr, Rm 2327B, Stanford, CA 94305-5821, USA. jason.gotlib@stanford.edu
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Case Reports
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