Linked Life Data

17363557

Source:http://linkedlifedata.com/resource/pubmed/id/17363557

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2007-3-16
pubmed:abstractText
The mammalian target of rapamycin (mTOR) is thought to play a critical role in regulating cell growth, cell cycle progression, and tumorigenesis. Because the AKT-mTOR pathway is frequently hyperactivated in ovarian cancer, we hypothesized that the mTOR inhibitor RAD001 (Everolimus) would inhibit ovarian tumorigenesis in transgenic mice that spontaneously develop ovarian carcinomas. We used TgMISIIR-TAg transgenic mice, which develop bilateral ovarian serous adenocarcinomas accompanied by ascites and peritoneal dissemination. Fifty-eight female TgMISIIR-TAg mice were treated with 5 mg/kg RAD001 or placebo twice weekly from 5 to 20 weeks of age. To monitor tumor development, mice were examined biweekly using magnetic resonance microimaging. In vivo effects of RAD001 on Akt-mTOR signaling, tumor cell proliferation, and blood vessel area were analyzed by immunohistochemistry and Western blot analysis. RAD001 treatment markedly delayed tumor development. Tumor burden was reduced by approximately 84%. In addition, ascites formation, together with peritoneal dissemination, was detected in only 21% of RAD001-treated mice compared with 74% in placebo-treated animals. Approximately 30% of RAD001-treated mice developed early ovarian carcinoma confined within the ovary, whereas all placebo-treated mice developed advanced ovarian carcinoma. Treatment with RAD001 diminished the expression of vascular endothelial growth factor in tumor-derived cell lines and inhibited angiogenesis in vivo. RAD001 also attenuated the expression of matrix metalloproteinase-2 and inhibited the invasiveness of tumor-derived cells. Taken together, these preclinical findings suggest that mTOR inhibition, alone or in combination with other molecularly targeted drugs, could represent a promising chemopreventive strategy in women at high familial risk of ovarian cancer.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
67
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2408-13
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:17363557-Animals, pubmed-meshheading:17363557-Disease Models, Animal, pubmed-meshheading:17363557-Disease Progression, pubmed-meshheading:17363557-Female, pubmed-meshheading:17363557-Matrix Metalloproteinase 2, pubmed-meshheading:17363557-Mice, pubmed-meshheading:17363557-Mice, Transgenic, pubmed-meshheading:17363557-Neovascularization, Pathologic, pubmed-meshheading:17363557-Ovarian Neoplasms, pubmed-meshheading:17363557-Phosphorylation, pubmed-meshheading:17363557-Protein Kinase Inhibitors, pubmed-meshheading:17363557-Protein Kinases, pubmed-meshheading:17363557-Proto-Oncogene Proteins c-akt, pubmed-meshheading:17363557-Signal Transduction, pubmed-meshheading:17363557-Sirolimus, pubmed-meshheading:17363557-TOR Serine-Threonine Kinases, pubmed-meshheading:17363557-Vascular Endothelial Growth Factor A
pubmed:year
2007
pubmed:articleTitle
RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer.
pubmed:affiliation
Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural