Document Detail

RET tyrosine kinase and medullary thyroid cells are unaffected by clinical doses of STI571.
MedLine Citation:
PMID:  14666655     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Activating mutations in the RET receptor tyrosine kinase are responsible for the development of medullary thyroid cancer (MTC) in persons with Multiple Endocrine Neoplasia type 2. We hypothesized that STI571 (Gleevec) would inhibit RET kinase and be a useful agent in the treatment of MTC. MATERIALS AND METHODS: We determined the IC50 of STI571 for RET using an in vitro kinase assay and also examined the effects of STI571 on cellular proliferation and viability in TT cells, a human MTC cell line. RESULTS: The average in vitro IC50 of STI571 for RET is 37 microM +/- 4 microM. Additionally, TT cells incubated with 10 microM STI571 for up to 8 days showed no apparent reduction in cell proliferation or viability. Higher concentrations of STI571, from 25 to 100 microM, induced necrosis of TT cells. CONCLUSION: The concentrations of STI571 required to significantly inhibit RET and to inhibit TT cell proliferation are not clinically achievable. We conclude that STI571 is not likely to be an effective treatment for MTC.
Michael A Skinner; Shawn D Safford; Alex J Freemerman
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anticancer research     Volume:  23     ISSN:  0250-7005     ISO Abbreviation:  Anticancer Res.     Publication Date:    2003 Sep-Oct
Date Detail:
Created Date:  2003-12-11     Completed Date:  2004-02-11     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8102988     Medline TA:  Anticancer Res     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  3601-6     Citation Subset:  IM    
Department of Surgery, Duke University, Durham, NC 27710, USA.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Carcinoma, Medullary / drug therapy*,  enzymology,  pathology
Cell Death / drug effects
Cell Division / drug effects
Cell Line, Tumor
Enzyme Inhibitors / pharmacology*
Inhibitory Concentration 50
Phosphorylation / drug effects
Piperazines / pharmacology*
Proto-Oncogene Proteins / antagonists & inhibitors*,  metabolism
Proto-Oncogene Proteins c-ret
Pyrimidines / pharmacology*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*,  metabolism
Thyroid Neoplasms / drug therapy*,  enzymology,  pathology
Reg. No./Substance:
0/Antineoplastic Agents; 0/Enzyme Inhibitors; 0/Piperazines; 0/Proto-Oncogene Proteins; 0/Pyrimidines; 152459-95-5/imatinib; EC Proteins c-ret; EC Protein-Tyrosine Kinases

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