Linked Life Data

21282335

Source:http://linkedlifedata.com/resource/pubmed/id/21282335

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2011-3-16
pubmed:abstractText
TGF-? is produced excessively by many solid tumors and can drive malignant progression through multiple effects on the tumor cell and microenvironment. TGF-? signaling pathway inhibitors have shown efficacy in preclinical models of metastatic cancer. Here, we investigated the effect of systemic LY2109761, a TGF-? type I/II receptor (T?RI/T?RII) kinase inhibitor, in both a tumor allograft model and the mouse skin model of de novo chemically induced carcinogenesis in vivo. Systemic LY2109761 administration disrupted tumor vascular architecture and reduced myofibroblast differentiation of E4 skin carcinoma cells in a tumor allograft. In the 7,12-dimethyl-benzanthracene plus phorbol myristate acetate-induced skin chemical carcinogenesis model, acute dosing of established naive primary carcinomas with LY2109761 (100 mg/kg) every 8 hours for 10 days (100 mg/kg) diminished phospho-Smad2 (P-Smad2) levels and marginally decreased the expression of inflammatory and invasive markers. Sustained exposure to LY2109761 (100 mg/kg/d) throughout the tumor outgrowth phase had no effect on carcinoma latency or incidence. However, molecular analysis of resultant carcinomas by microarray gene expression, Western blotting, and immunohistochemistry suggests that long-term LY2109761 exposure leads to the outgrowth of carcinomas with elevated P-Smad2 levels that do not respond to drug. This is the first description of acquired resistance to a small-molecule inhibitor of the T?RI/T?RII kinase. Resultant carcinomas were more aggressive and inflammatory in nature, with delocalized E-cadherin and elevated expression of Il23a, laminin V, and matrix metalloproteinases. Therefore, TGF-? inhibitors might be clinically useful for applications requiring acute administration, but long-term patient exposure to such drugs should be undertaken with caution.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1538-7445
pubmed:author
pubmed:copyrightInfo
© 2011 AACR.
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
71
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2339-49
pubmed:dateRevised
2011-9-26
pubmed:meshHeading
pubmed-meshheading:21282335-Animals, pubmed-meshheading:21282335-Blotting, Western, pubmed-meshheading:21282335-Cadherins, pubmed-meshheading:21282335-Carcinoma, Squamous Cell, pubmed-meshheading:21282335-Cell Line, Tumor, pubmed-meshheading:21282335-Cell Proliferation, pubmed-meshheading:21282335-Drug Resistance, Neoplasm, pubmed-meshheading:21282335-Epithelial-Mesenchymal Transition, pubmed-meshheading:21282335-Female, pubmed-meshheading:21282335-Gene Expression Profiling, pubmed-meshheading:21282335-Gene Expression Regulation, Neoplastic, pubmed-meshheading:21282335-Immunohistochemistry, pubmed-meshheading:21282335-Male, pubmed-meshheading:21282335-Mice, pubmed-meshheading:21282335-Myofibroblasts, pubmed-meshheading:21282335-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:21282335-Papilloma, pubmed-meshheading:21282335-Phosphorylation, pubmed-meshheading:21282335-Protein-Serine-Threonine Kinases, pubmed-meshheading:21282335-Pyrazoles, pubmed-meshheading:21282335-Pyrroles, pubmed-meshheading:21282335-Receptors, Transforming Growth Factor beta, pubmed-meshheading:21282335-Smad2 Protein, pubmed-meshheading:21282335-Time Factors
pubmed:year
2011
pubmed:articleTitle
Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long-term T?RI/II kinase inhibition with LY2109761.
pubmed:affiliation
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural