Linked Life Data

16001956

Source:http://linkedlifedata.com/resource/pubmed/id/16001956

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2005-7-8
pubmed:abstractText
Insulin-like growth factors (IGF) and their receptors (IGF-1R) constitute a complex biologic system implicated in diverse regulatory levels of cell proliferation, viability, differentiation and metabolism. Extensive epidemiologic data have implicated the IGF/IGF-1R pathway in the establishment of human malignancies, consistent with experimental data on the role of this signaling cascade in promoting cell transformation, resistance to apoptosis, metastases and other aspects of the biology of human cancers. However, historically, the IGF/IGF-1R pathway has not been viewed as an attractive target for therapeutic intervention. The widespread IGF-1R expression in normal tissues and its close homology to the insulin receptor had led to the assumption that IGF-1R inhibition would cause unacceptable toxicities in vivo. Even though neutralizing antibodies against human IGF-1R have been efficacious against xenograft tumors, a lack of reactivity against the host rodent receptor has confounded the assessment of its therapeutic index. Furthermore, the lack of a clear understanding of the relevant significance for neoplastic cells in the function of IGF-1R versus other growth factor receptors provided an additional disincentive for the study of this pathway. However, recent reports from the authors' group and others have shown that small molecule inhibitors of tyrosine kinase activity of IGF-1R can be safely and efficaciously administered in vivo in clinically relevant orthotopic models of human neoplasias, such as multiple myeloma. This article reviews the data that validated IGF-1R as a therapeutic target for a broad spectrum of malignancies and provides in vivo proof-of-concept for the use of selective IGF-1R kinase inhibitors as primary antitumor therapy or in synergistic combination as chemosensitizers. These results have not only provided the rationale for clinical trials of small molecule IGF-1R inhibitors, but have also rekindled interest in other therapeutic modalities (e.g., monoclonal antibodies) aimed at suppressing the function of this critical pathway for tumor cell pathophysiology.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1744-8328
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
5
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
487-99
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Treatment of hematologic malignancies and solid tumors by inhibiting IGF receptor signaling.
pubmed:affiliation
Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Department of Medicine, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. Constantine_Mitsiades@dfci.harvard.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Review, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural