title: Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit.
abstract: OBJECTIVE
  STI571 is a tyrosine kinase inhibitor which inhibits the kinase activity of kit, the receptor for stem cell factor (SCF). Because activating mutations of c-kit affecting codon 816 are associated with human mast cell neoplasms, we determined whether STI571 exerted a similar cytotoxic effect on neoplastic and normal human mast cells.
  
  
  METHODS
  We investigated the effect of addition of STI571 in increasing concentrations (0.01 to 10 micromolar) to two HMC-1 human mast cell leukemia cell lines carrying two different activating c-kit mutations in codons 816 or 560, as well as the effect of the drug on short-term bone marrow cultures obtained from patients who carry a mutated codon 816 or wild-type c-kit.
  
  
  RESULTS
  STI571 failed to inhibit the growth of HMC-1(560,816) cells bearing a codon 816 mutation but effectively suppressed the proliferation of HMC-1(560) carrying c-kit with the wild-type codon 816. STI571 did not induce preferential killing of neoplastic bone marrow mast cells in short-term cultures from patients bearing a codon 816 c-kit mutation. In contrast, STI571 caused a dramatic reduction in mast cells in patients without codon 816 c-kit mutations.
  
  
  CONCLUSIONS
  These results suggest that STI571, while effectively killing mast cells with wild-type c-kit, did not show preferential cytotoxicity to neoplastic human mast cells and thus may not be effective in the treatment of human systemic mastocytosis associated with codon 816 c-kit mutations.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1881, USA. cakin@niaid.nih.gov
authors.forename: Cem
authors.initials: C
authors.lastname: Akin
authors.forename: Knut
authors.initials: K
authors.lastname: Brockow
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Ambrosio
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Kirshenbaum
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Ma
authors.forename: B Jack
authors.initials: BJ
authors.lastname: Longley
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D001549:Benzamides; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003062:Codon / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D008415:Mastocytosis / Q000473:pathology; D008875:Middle Aged; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D001549:Benzamides; D003062:Codon; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D016044:Fusion Proteins, bcr-abl