Linked Life Data

15849741

Source:http://linkedlifedata.com/resource/pubmed/id/15849741

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2005-8-3
pubmed:abstractText
The acute apoptotic response to genotoxic carcinogens (AARGC) might be important for controlling the subsequent colonic mutational load and progression through oncogenesis. We have found previously that AARGC is p53-dependent with a gene-dosage effect, and that decreased AARGC in p53(+/-) and p53(-/-) mice is associated with increased susceptibility to carcinogen-induced oncogenesis. We tested the ability of sulindac to reverse these defects. The effect of sulindac on azoxymethane (AOM)-induced apoptosis was measured in colonic epithelium in wild-type, p53(+/-) and p53(-/-) mice, 8 hr after a single AOM injection. Sulindac supplementation (0.5 +/- 0.1 mg/day) restored defective AARGC in p53(+/-) but not in p53(-/-) mice. For effect on colon tumor development, sulindac treatment was started at age 4 weeks in wild-type, p53(+/-) and p53(-/-) mice; three weekly AOM injections were commenced at 6 weeks of age to induce tumors. Sulindac reduced significantly tumor incidence and multiplicity in wild-type mice (17% and 0.3 tumors/mouse compared to 36% and 0.8 respectively without drug), in p53(+/-)mice (38% and 0.8 compared to 64% and 1.63) and in p53(-/-) mice (63% and 1.0 compared to 90% and 1.74). Although loss of p53 function impairs the apoptotic response to AOM-induced DNA damage, sulindac is capable of partly restoring this defect. As sulindac also reverses the increased risk of oncogenesis due to p53 dysfunction, its enhancement of the apoptotic response to initiating mutations might act to reduce mutational load driving oncogenesis. Sulindac is an effective chemopreventive agent in the presence of p53 dysfunction.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0020-7136
pubmed:author
pubmed:issnType
Print
pubmed:day
10
pubmed:volume
116
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
870-5
pubmed:dateRevised
2007-7-24
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Sulindac corrects defective apoptosis and suppresses azoxymethane-induced colonic oncogenesis in p53 knockout mice.
pubmed:affiliation
Department of Medicine Flinders University of South Australia, Adelaide, Australia. ying.hu@flinders.edu.au
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't