Linked Life Data

15001986

Source:http://linkedlifedata.com/resource/pubmed/id/15001986

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2004-3-5
pubmed:abstractText
Mutations in the tumor-suppressor gene p53 have been associated with advanced colorectal cancer (CRC). Irinotecan (CPT-11), a DNA topoisomerase 1 inhibitor, has been recently incorporated to the adjuvant therapy. Since the DNA-damage checkpoint depends on p53 activation, the status of p53 might critically influence the response to CPT-11. We analysed the sensitivity to CPT-11 in the human colon cancer cell line HT29 (mut p53) and its wild-type (wt)-p53 stably transfected subclone HT29-A4. Cell-cycle analysis in synchronised cells demonstrated the activation of transfected wt-p53 and a p21(WAF1/CIP1)-dependent cell-cycle blockage in the S phase. Activated wt-p53 increased apoptosis and enhanced sensitivity to CPT-11. In p53-deficient cells, cDNA-macroarray analysis and western blotting showed an accumulation of the cyclin-dependent kinase (cdk)1/cyclin B complex. Subsequent p53-independent activation of the cdk-inhibitor (cdk-I) p21(WAF1/CIP1) prevented cell-cycle progression. Cdk1 induction was exploited in vivo to improve the sensitivity to CPT-11 by additional treatment with the cdk-I CYC-202. We demonstrate a gain of sensitivity to CPT-11 in a p53-mutated colon cancer model either by restoring wild-type p53 function or by sequential treatment with cdk-Is. Considering that mutations in p53 are among the most common genetic alterations in CRC, a therapeutic approach specifically targeting p53-deficient tumors could greatly improve the treatment outcomes.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0950-9232
pubmed:author
pubmed:issnType
Print
pubmed:day
4
pubmed:volume
23
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1737-44
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53-deficient HT29 human colon cancer cell line.
pubmed:affiliation
Transfer Laboratory, Institut Curie-CNRS, Paris 75248, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't