Source:http://linkedlifedata.com/resource/pubmed/id/12566306
Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
3
|
| pubmed:dateCreated |
2003-2-4
|
| pubmed:abstractText |
Insulin-like growth factors (IGFs) stimulate breast cancer proliferation, motility, and survival. The type I IGF receptor (IGF1R) mediates the effects of IGF-I. Thus, inhibition of IGF1R activation could inhibit IGF action in breast cancer cells. A single-chain antibody directed against IGF1R (IGF1R scFv-Fc) has been shown to partially inhibit xenograft growth of MCF-7 cells in athymic mice. In this study, we have examined the effects of scFv-Fc on IGF1R signaling in the estrogen receptor-positive (ER+) MCF-7 breast cancer cells in vitro and in vivo. The antibody stimulated IGF1R activation in vitro in MCF-7 cells and was unable to block IGF-I effects. The antibody also stimulated proliferation of MCF-7 cells in monolayer growth assays. To determine how scFv-Fc could stimulate in vitro growth yet inhibit in vivo tumor growth, we examined the effect of scFv-Fc on IGF1R expression. In MCF-7 cells, scFv-Fc down-regulated IGF1R levels after 2 h, and the levels were greatly reduced after 24 h. In contrast, IGF-I treatment over the same time period did not affect IGF1R levels. Twenty-four-h pretreatment of cells with scFv-Fc blocked IGF-I mediated phosphorylation of insulin receptor substrate-1 and subsequent extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 and phosphatidylinositol 3'-kinase activation. In contrast, cells treated with 5 nM IGF-I for 24 h still retained the ability to further activate downstream signaling pathways in response to IGF-I. Moreover, pretreatment of MCF-7 cells with scFv-Fc rendered them refractory to further proliferation induced by additional IGF-I. Twenty-four-h pretreatment of cells with scFv-Fc also inhibited IGF-I stimulated anchorage-independent growth. scFv-Fc did not enhance antibody-dependent cell-mediated cytotoxicity. In vivo, treatment of mice bearing MCF-7 xenograft tumors with scFv-Fc resulted in near complete down-regulation of IGF1R. Our data show that scFv-Fc stimulates biochemical activation of IGF1R, then causes receptor down-regulation, making MCF-7 cells refractory to additional IGF-I exposure. These results indicate that such chimeric single-chain antibodies against IGF1R have future potential in breast cancer therapy by causing down-regulation of receptor.
|
| pubmed:grant | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal,
http://linkedlifedata.com/resource/pubmed/chemical/Immunoglobulin Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/Immunoglobulin G,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin Receptor Substrate Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin-Like Growth Factor I,
http://linkedlifedata.com/resource/pubmed/chemical/Irs1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, IGF Type 1,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Feb
|
| pubmed:issn |
0008-5472
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
1
|
| pubmed:volume |
63
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
627-35
|
| pubmed:dateRevised |
2010-11-18
|
| pubmed:meshHeading |
pubmed-meshheading:12566306-3T3 Cells,
pubmed-meshheading:12566306-Animals,
pubmed-meshheading:12566306-Antibodies, Monoclonal,
pubmed-meshheading:12566306-Breast Neoplasms,
pubmed-meshheading:12566306-Cell Adhesion,
pubmed-meshheading:12566306-Cell Division,
pubmed-meshheading:12566306-Down-Regulation,
pubmed-meshheading:12566306-Female,
pubmed-meshheading:12566306-Immunoglobulin Fragments,
pubmed-meshheading:12566306-Immunoglobulin G,
pubmed-meshheading:12566306-Insulin Receptor Substrate Proteins,
pubmed-meshheading:12566306-Insulin-Like Growth Factor I,
pubmed-meshheading:12566306-MAP Kinase Signaling System,
pubmed-meshheading:12566306-Mice,
pubmed-meshheading:12566306-Mice, Nude,
pubmed-meshheading:12566306-Mitogen-Activated Protein Kinases,
pubmed-meshheading:12566306-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:12566306-Phosphoproteins,
pubmed-meshheading:12566306-Phosphorylation,
pubmed-meshheading:12566306-Receptor, IGF Type 1,
pubmed-meshheading:12566306-Recombinant Fusion Proteins,
pubmed-meshheading:12566306-Signal Transduction,
pubmed-meshheading:12566306-Tumor Cells, Cultured,
pubmed-meshheading:12566306-Xenograft Model Antitumor Assays
|
| pubmed:year |
2003
|
| pubmed:articleTitle |
A chimeric humanized single-chain antibody against the type I insulin-like growth factor (IGF) receptor renders breast cancer cells refractory to the mitogenic effects of IGF-I.
|
| pubmed:affiliation |
Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota 55455, USA.
|
| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't
|