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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
2
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pubmed:dateCreated |
1998-8-31
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pubmed:abstractText |
Postreplicative mismatch repair plays a major role in mediating the cytotoxicity of agents generating O6-methylguanine in DNA. We previously showed that a methylating antitumor triazene compound, temozolomide, induces apoptosis and that the persistence of O6-methylguanine in DNA is required to trigger the process. We wanted to test whether the latter apoptotic signal is dependent on a functional mismatch repair system. To this end, we used two human lymphoblastoid cell lines (i.e., the mismatch repair-proficient TK6 line and its mismatch repair-deficient subline MT1) that are both deficient in O6-methylguanine repair. Temozolomide treatment of TK6 cells brought about efficient cell growth inhibition, G2/M arrest, and apoptosis, as indicated by the results of cytofluorimetric analysis of 5-bromo-2'-deoxyuridine incorporation and DNA content and evaluation of DNA fragmentation. The drug treatment resulted also in the induction of p53 and p21/waf-1 protein expression. In contrast, MT1 cells were highly resistant to the drug and no p53 and p21/waf-1 induction was observed. Importantly, we could show that MT1 cells are not deficient in the p53-dependent apoptosis pathway; treatment with etoposide, a topoisomerase II inhibitor, resulted in p53 and p21/waf-1 protein expression and apoptosis in both cell lines. In conclusion, we demonstrate the existence of a link between a functional mismatch repair system and the trigger of apoptosis in cells exposed to clinically relevant concentrations of temozolomide. The results also suggest that p53 induction in response to O6-guanine methylation involves the mismatch repair system.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Alkylating,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Phytogenic,
http://linkedlifedata.com/resource/pubmed/chemical/CDKN1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclins,
http://linkedlifedata.com/resource/pubmed/chemical/Dacarbazine,
http://linkedlifedata.com/resource/pubmed/chemical/Etoposide,
http://linkedlifedata.com/resource/pubmed/chemical/Nucleic Acid Heteroduplexes,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Protein p53,
http://linkedlifedata.com/resource/pubmed/chemical/temozolomide
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0026-895X
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
54
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
334-41
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:9687575-Antineoplastic Agents, Alkylating,
pubmed-meshheading:9687575-Antineoplastic Agents, Phytogenic,
pubmed-meshheading:9687575-Apoptosis,
pubmed-meshheading:9687575-Cell Cycle,
pubmed-meshheading:9687575-Cell Division,
pubmed-meshheading:9687575-Cyclin-Dependent Kinase Inhibitor p21,
pubmed-meshheading:9687575-Cyclins,
pubmed-meshheading:9687575-DNA Repair,
pubmed-meshheading:9687575-Dacarbazine,
pubmed-meshheading:9687575-Etoposide,
pubmed-meshheading:9687575-Humans,
pubmed-meshheading:9687575-Nucleic Acid Heteroduplexes,
pubmed-meshheading:9687575-Tumor Cells, Cultured,
pubmed-meshheading:9687575-Tumor Suppressor Protein p53
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pubmed:year |
1998
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pubmed:articleTitle |
Involvement of the mismatch repair system in temozolomide-induced apoptosis.
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pubmed:affiliation |
Istituto Dermopatico Dell'Immacolata, Rome, Italy. s.datri@idi.it
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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