title: RET tyrosine kinase and medullary thyroid cells are unaffected by clinical doses of STI571.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27710, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Skinner
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Safford
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Freemerman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D018276:Carcinoma, Medullary / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D011743:Pyrimidines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases