Linked Life Data

19903855

Source:http://linkedlifedata.com/resource/pubmed/id/19903855

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
22
pubmed:dateCreated
2009-11-13
pubmed:abstractText
Lung cancer is the commonest cancer killer. Small cell lung cancer (SCLC) is initially chemosensitive, but rapidly relapses in a chemoresistant form with an overall survival of <5%. Consequently, novel therapies are urgently required and will likely arise from an improved understanding of the disease biology. Our previous work showed that fibroblast growth factor-2 induces proliferation and chemoresistance in SCLC cells. Here, we show that the selective fibroblast growth factor receptor (FGFR) inhibitor PD173074 blocks H-510 and H-69 SCLC proliferation and clonogenic growth in a dose-dependent fashion and prevents FGF-2-induced chemoresistance. These effects correlate with the inhibition of both FGFR1 and FGFR2 transphosphorylation. We then determined the efficacy of daily oral administration of PD173074 for 28 days in two human SCLC models. In the H-510 xenograft, tumor growth was impaired similar to that seen with single-agent cisplatin administration, increasing median survival compared with control sham-treated animals. Crucially, the effect of cisplatin was significantly potentiated by coadministration of PD173074. More dramatically, in H-69 xenografts, PD173074 induced complete responses lasting >6 months in 50% of mice. These effects were not a consequence of disrupted tumor vasculature but instead correlated with increased apoptosis (caspase 3 and cytokeratin 18 cleavage) in excised tumors. Moreover, in vivo imaging with 3'-deoxy-3'-[(18)F]fluorothymidine-positron emission tomography ([(18)F]FLT-PET) showed decreased intratumoral proliferation in live animals treated with the compound at 7 to 14 days. Our results suggest that clinical trials of FGFR inhibitors should be undertaken in patients with SCLC and that [(18)F]FLT-PET imaging could provide early in vivo evidence of response.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1538-7445
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
69
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
8645-51
pubmed:meshHeading
pubmed-meshheading:19903855-Animals, pubmed-meshheading:19903855-Antineoplastic Agents, pubmed-meshheading:19903855-Blotting, Western, pubmed-meshheading:19903855-Cell Proliferation, pubmed-meshheading:19903855-Cisplatin, pubmed-meshheading:19903855-Drug Resistance, Neoplasm, pubmed-meshheading:19903855-Drug Synergism, pubmed-meshheading:19903855-Fibroblast Growth Factor 2, pubmed-meshheading:19903855-Humans, pubmed-meshheading:19903855-Immunohistochemistry, pubmed-meshheading:19903855-In Situ Hybridization, Fluorescence, pubmed-meshheading:19903855-Lung Neoplasms, pubmed-meshheading:19903855-Mice, pubmed-meshheading:19903855-Positron-Emission Tomography, pubmed-meshheading:19903855-Pyrimidines, pubmed-meshheading:19903855-Receptors, Fibroblast Growth Factor, pubmed-meshheading:19903855-Small Cell Lung Carcinoma, pubmed-meshheading:19903855-Transfection, pubmed-meshheading:19903855-Xenograft Model Antitumor Assays
pubmed:year
2009
pubmed:articleTitle
The fibroblast growth factor receptor inhibitor PD173074 blocks small cell lung cancer growth in vitro and in vivo.
pubmed:affiliation
Lung Cancer Biology Group, Cancer Research UK Laboratories, Clinical Sciences Centre, Hammersmith Hospital Campus of Imperial College London, London, United Kingdom.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't