Document Detail


Inhibition of the growth of papillary thyroid carcinoma cells by CI-1040.
MedLine Citation:
PMID:  19380355     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Papillary thyroid carcinoma (PTC), the most common type of thyroid malignancy, usually possesses mutations, either RET/PTC rearrangement or BRAF mutation. Both mutations can activate the mitogen-activated protein kinase kinase/extracellular signal-related kinase signaling transduction pathway, which results in activation of transcription factors that regulate cellular proliferation, differentiation, and apoptosis.
OBJECTIVE: To test the effects of CI-1040 (PD184352), a specific MEK1/2 inhibitor, on PTC cells carrying either an RET/PTC1 rearrangement or a BRAF mutation.
DESIGN: The effects of CI-1040 on PTC cells were evaluated in vitro and in vivo.
MAIN OUTCOME MEASURES: The effects of CI-1040 on PTC cells were evaluated in vitro using a cell proliferation assay, cell cycle analysis, and immunoblotting. The antitumor effects of CI-1040 in vivo were evaluated in an orthotopic mouse model.
RESULTS: The concentrations of CI-1040 needed to inhibit 50% cell growth were 0.052microM for PTC cells with a BRAF mutation and 1.1microM for PTC cells with the RET/PTC1 rearrangement. After 3 weeks of oral administration of CI-1040 (300 mg/kg/d) to mice with orthotopic tumor implants of PTC cells, the mean tumor volume of implants bearing the RET/PTC1 rearrangement (n = 5) was reduced 47.5% compared with untreated mice (from 701.9 to 368.5 mm(3)), and the mean volume of implants with a BRAF mutation (n = 8) was reduced 31.3% (from 297.3 to 204.2 mm(3)).
CONCLUSIONS: CI-1040 inhibits PTC cell growth in vitro and in vivo. Because RET/PTC rearrangements are unique to thyroid carcinomas and a high percentage of PTCs possess either mutation, these findings support the clinical evaluation of CI-1040 for patients with PTC.
Authors:
Ying C Henderson; Soon-Hyun Ahn; Gary L Clayman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Archives of otolaryngology--head & neck surgery     Volume:  135     ISSN:  1538-361X     ISO Abbreviation:  Arch. Otolaryngol. Head Neck Surg.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-04-21     Completed Date:  2009-05-28     Revised Date:  2012-06-21    
Medline Journal Info:
Nlm Unique ID:  8603209     Medline TA:  Arch Otolaryngol Head Neck Surg     Country:  United States    
Other Details:
Languages:  eng     Pagination:  347-54     Citation Subset:  AIM; IM    
Affiliation:
Department of Head and Neck Surgery, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 441, Houston, TX 77030, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Benzamides / pharmacology*
Carcinoma, Papillary / drug therapy*,  genetics,  pathology
Cell Line, Tumor
Cell Proliferation / drug effects*
Disease Models, Animal
Enzyme Inhibitors / pharmacology*
Gene Rearrangement
MAP Kinase Kinase Kinase 1 / antagonists & inhibitors
Mice
Mice, Nude
Mutation
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins c-ret / genetics
Thyroid Neoplasms / drug therapy*,  genetics,  pathology
Grant Support
ID/Acronym/Agency:
1P50-CA-97007/CA/NCI NIH HHS; 5P30 CA 16672/CA/NCI NIH HHS; CA 16672/CA/NCI NIH HHS; R01 DE-13954/DE/NIDCR NIH HHS
Chemical
Reg. No./Substance:
0/2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; 0/Benzamides; 0/Enzyme Inhibitors; EC 2.7.10.1/Proto-Oncogene Proteins c-ret; EC 2.7.10.1/RET protein, human; EC 2.7.11.1/BRAF protein, human; EC 2.7.11.1/Proto-Oncogene Proteins B-raf; EC 2.7.11.25/MAP Kinase Kinase Kinase 1

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