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rdf:type |
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lifeskim:mentions |
umls-concept:C0001128,
umls-concept:C0007634,
umls-concept:C0010656,
umls-concept:C0021467,
umls-concept:C0021469,
umls-concept:C0040085,
umls-concept:C0085862,
umls-concept:C0441655,
umls-concept:C0442805,
umls-concept:C0657233,
umls-concept:C0686907,
umls-concept:C0851827,
umls-concept:C0871261,
umls-concept:C1299583,
umls-concept:C1326205,
umls-concept:C1549571,
umls-concept:C1608386,
umls-concept:C1701901,
umls-concept:C1704632,
umls-concept:C1706817,
umls-concept:C1882074,
umls-concept:C2261841,
umls-concept:C2346927,
umls-concept:C2825492,
umls-concept:C2911692
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pubmed:issue |
11
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pubmed:dateCreated |
1998-6-26
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pubmed:abstractText |
Thymidylate synthase (TS) inhibition causes cell death, and this enzyme is the target for the important chemotherapy regime 5-fluorouracil/leucovorin. GW1843 (1843U89) is a potent and specific folate analog TS inhibitor in clinical development. Because of the importance of TS as a chemotherapy target, we are studying the mechanism of TS inhibition-induced cell death by GW1843. Ceramide is a regulatory lipid generated by the action of sphingomyelinase and is believed to signal apoptosis. The role of the ceramide in apoptotic signaling was studied in Molt-4 human T-cell leukemia cells undergoing cell death after treatment with GW1843. In response to GW1843, Molt-4 cells undergo apoptosis with both acidic pH, Mg2+-independent sphingomyelinase (ASMase) and neutral pH, Mg2+-dependent sphingomyelinase (NSMase) activities elevated as early steps in the initiation of apoptosis before Molt-4 commitment to death. These activities lead to ceramide production with kinetics consistent with a role as an effector molecule signaling the initiation of apoptosis in Molt-4 cells. These changes were found to be independent of caspase 3-like (CPP32/apopain) activity and DNA degradation, but were not separable from membrane blebbing or cell lysis in this cell line. In this report, kinetic evidence is provided for a role of ceramide in initiating GW1843-induced cell death of Molt-4 T-cell leukemia cells.
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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 |
http://linkedlifedata.com/resource/pubmed/chemical/1843U89,
http://linkedlifedata.com/resource/pubmed/chemical/CASP3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Caspases,
http://linkedlifedata.com/resource/pubmed/chemical/Ceramides,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Diglycerides,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Precursors,
http://linkedlifedata.com/resource/pubmed/chemical/Indoles,
http://linkedlifedata.com/resource/pubmed/chemical/Isoindoles,
http://linkedlifedata.com/resource/pubmed/chemical/Magnesium,
http://linkedlifedata.com/resource/pubmed/chemical/Quinazolines,
http://linkedlifedata.com/resource/pubmed/chemical/Sphingomyelin Phosphodiesterase,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidylate Synthase
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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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 |
91
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4350-60
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:9596684-Apoptosis,
pubmed-meshheading:9596684-Caspase 3,
pubmed-meshheading:9596684-Caspases,
pubmed-meshheading:9596684-Ceramides,
pubmed-meshheading:9596684-Cysteine Endopeptidases,
pubmed-meshheading:9596684-Diglycerides,
pubmed-meshheading:9596684-Enzyme Inhibitors,
pubmed-meshheading:9596684-Enzyme Precursors,
pubmed-meshheading:9596684-Humans,
pubmed-meshheading:9596684-Indoles,
pubmed-meshheading:9596684-Isoindoles,
pubmed-meshheading:9596684-Leukemia, T-Cell,
pubmed-meshheading:9596684-Magnesium,
pubmed-meshheading:9596684-Quinazolines,
pubmed-meshheading:9596684-Sphingomyelin Phosphodiesterase,
pubmed-meshheading:9596684-Thymidylate Synthase,
pubmed-meshheading:9596684-Tumor Cells, Cultured
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pubmed:year |
1998
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pubmed:articleTitle |
Increases in neutral, Mg2+-dependent and acidic, Mg2+-independent sphingomyelinase activities precede commitment to apoptosis and are not a consequence of caspase 3-like activity in Molt-4 cells in response to thymidylate synthase inhibition by GW1843.
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pubmed:affiliation |
International Science Development Group, Glaxo Wellcome Inc, Research Triangle Park, NC 27709, USA.
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pubmed:publicationType |
Journal Article
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