rdf:type |
|
lifeskim:mentions |
umls-concept:C0002073,
umls-concept:C0011155,
umls-concept:C0017262,
umls-concept:C0185117,
umls-concept:C0235782,
umls-concept:C0332324,
umls-concept:C1155873,
umls-concept:C1334505,
umls-concept:C1518174,
umls-concept:C1704807,
umls-concept:C2911684
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pubmed:issue |
6
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pubmed:dateCreated |
2005-5-4
|
pubmed:abstractText |
The aim of this study was to assess whether combined evaluation of O6-methylguanine methyltransferase (MGMT) and hMLH1 status determines sensitivity to monofuntional alkylating agents such as N-methyl-N-nitrosourea (MNU) and dacarbazine (DTIC) against gallbladder carcinoma cells. The molecular mechanism behind MGMT and hMLH1 status affecting the cell cycle was also addressed. Using 5 gallbladder cancer carcinoma lines and 1 colon carcinoma cell line (SW48), MGMT and hMLH1 expression was analyzed using RT-PCR and Western blotting. MGMT and hMLH1 status in the 6 cell lines was compared with drug sensitivity to MNU. As a result, cell lines that were MGMT-/hMLH1+ had the highest sensitivity to MNU, compared with MGMT+/hMLH1+ and MGMT-/hMLH1- cells. In flow cytometric analysis, G2-M cell cycle arrest was specifically observed in GB-d1 cells with MGMT-/hMLH1+ and expression of cyclin A and Cdc2 in GB-d1 cells was significantly reduced by MNU treatment, but not observed in KMG-C cells with MGMT+/hMLH1+. Finally, we assessed the in vitro and in vivo effect of the clinically used alkylating agent DTIC in these cells. The highest sensitivity to DTIC was also observed in MGMT-/hMLH1+. In conclusion, MNU suppressed cell proliferation of MGMT-/hMLH1+ gallbladder carcinoma cells by arresting the cell cycle at the G2-M phase, accompanied by down-regulation of cyclin A and Cdc2. These results indicated that expression of MGMT and hMLH1 could be used to select candidates for alkylating agent chemotherapy against gallbladder carcinoma.
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pubmed:language |
eng
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pubmed:journal |
|
pubmed:citationSubset |
IM
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adaptor Proteins, Signal Transducing,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Alkylating,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Dacarbazine,
http://linkedlifedata.com/resource/pubmed/chemical/MLH1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Methylnitrosourea,
http://linkedlifedata.com/resource/pubmed/chemical/Mlh1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/O(6)-Methylguanine-DNA...,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
|
pubmed:issn |
1019-6439
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pubmed:author |
|
pubmed:issnType |
Print
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pubmed:volume |
26
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pubmed:owner |
NLM
|
pubmed:authorsComplete |
Y
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pubmed:pagination |
1653-61
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:15870882-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:15870882-Animals,
pubmed-meshheading:15870882-Antineoplastic Agents, Alkylating,
pubmed-meshheading:15870882-Carrier Proteins,
pubmed-meshheading:15870882-Cell Division,
pubmed-meshheading:15870882-Cell Line, Tumor,
pubmed-meshheading:15870882-Dacarbazine,
pubmed-meshheading:15870882-Female,
pubmed-meshheading:15870882-Flow Cytometry,
pubmed-meshheading:15870882-G2 Phase,
pubmed-meshheading:15870882-Gallbladder Neoplasms,
pubmed-meshheading:15870882-Humans,
pubmed-meshheading:15870882-Methylnitrosourea,
pubmed-meshheading:15870882-Mice,
pubmed-meshheading:15870882-Mice, Inbred BALB C,
pubmed-meshheading:15870882-Neoplasm Proteins,
pubmed-meshheading:15870882-Neoplasms, Experimental,
pubmed-meshheading:15870882-Nuclear Proteins,
pubmed-meshheading:15870882-O(6)-Methylguanine-DNA Methyltransferase,
pubmed-meshheading:15870882-RNA, Messenger
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pubmed:year |
2005
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pubmed:articleTitle |
Deficient MGMT and proficient hMLH1 expression renders gallbladder carcinoma cells sensitive to alkylating agents through G2-M cell cycle arrest.
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pubmed:affiliation |
Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.
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pubmed:publicationType |
Journal Article
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