Linked Life Data

15809756

Source:http://linkedlifedata.com/resource/pubmed/id/15809756

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2005-4-5
pubmed:abstractText
O(6)-methylguanine methyltransferase (MGMT) repairs O(6)-alkylguanine in cellular DNA introduced by the clinically used alkylating drug 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU). Thus, cancer cells with MGMT expression are resistant to ACNU treatment. Cisplatin has been reported to suppress MGMT expression; however, the molecular mechanism by which cisplatin reduces MGMT expression remains to be elucidated. Using gallbladder cancer cells (KMG-C) expressing MGMT, we analyzed whether a low dose of cisplatin suppresses MGMT expression, followed by an enhanced drug effect of ACNU in vitro and in vivo. We also investigated the promoter region critical for the transcriptional repression of MGMT gene by cisplatin using 5 deletion mutants in reporter promoter assays. In RT-PCR analysis, the expression of MGMT mRNA in KMG-C cells was dose- and time-dependently repressed. Drug sensitivity to ACNU was increased 2-fold by pretreatment with cisplatin, compared with only ACNU treatment, in MTT assays as well as tumor-bearing nude mice. Although the 5'-flanking region is deleted as far as -69 bp upstream of the transcription start site, cisplatin dose dependently inhibited luciferase activity. However, cisplatin did not cause such repression when 59 bp region from -69 to -10 bp was deleted. We confirmed that cisplatin enhanced sensitivity to ACNU in KMG-C cells expressing MGMT both in vitro and in vivo. Furthermore, a low dose of cisplatin repressed the transcription of the MGMT promoter. The 59 bp region in the MGMT promoter was crucial for repression by cisplatin. These results might form the basis of a chemotherapeutic strategy involving alkylating agents via prior cisplatin-induced biochemical modulation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1021-335X
pubmed:author
pubmed:issnType
Print
pubmed:volume
13
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
899-906
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:15809756-Antineoplastic Agents, pubmed-meshheading:15809756-Base Sequence, pubmed-meshheading:15809756-Cell Line, Tumor, pubmed-meshheading:15809756-Cisplatin, pubmed-meshheading:15809756-DNA Primers, pubmed-meshheading:15809756-Gallbladder Neoplasms, pubmed-meshheading:15809756-Gene Expression Regulation, Enzymologic, pubmed-meshheading:15809756-Gene Expression Regulation, Neoplastic, pubmed-meshheading:15809756-Genes, Reporter, pubmed-meshheading:15809756-Humans, pubmed-meshheading:15809756-Molecular Sequence Data, pubmed-meshheading:15809756-Nimustine, pubmed-meshheading:15809756-O(6)-Methylguanine-DNA Methyltransferase, pubmed-meshheading:15809756-Plasmids, pubmed-meshheading:15809756-Promoter Regions, Genetic, pubmed-meshheading:15809756-Restriction Mapping, pubmed-meshheading:15809756-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:15809756-Sequence Deletion, pubmed-meshheading:15809756-Transcription, Genetic
pubmed:year
2005
pubmed:articleTitle
Cisplatin represses transcriptional activity from the minimal promoter of the O6-methylguanine methyltransferase gene and increases sensitivity of human gallbladder cancer cells to 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-2-chloroethyl)-3-nitrosourea.
pubmed:affiliation
Department of Surgery, Saga University Faculty of Medicine, Nabeshima 5-1-1, Saga 849-8501, Japan.
pubmed:publicationType
Journal Article