Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit

Exp Hematol. 2003 Aug;31(8):686-92. doi: 10.1016/s0301-472x(03)00112-7.


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.

Conclusion: 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.

MeSH terms

  • Adult
  • Aged
  • Amino Acid Substitution
  • Benzamides
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Cells, Cultured / drug effects
  • Cells, Cultured / metabolism
  • Codon / genetics
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Humans
  • Imatinib Mesylate
  • K562 Cells / drug effects
  • K562 Cells / metabolism
  • Male
  • Mast Cells / drug effects*
  • Mast Cells / metabolism
  • Mastocytosis / pathology
  • Middle Aged
  • Mutation, Missense
  • Neoplasm Proteins / antagonists & inhibitors
  • Piperazines / pharmacology*
  • Proto-Oncogene Proteins c-kit / analysis*
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism
  • Pyrimidines / pharmacology*
  • U937 Cells / drug effects
  • U937 Cells / metabolism


  • Benzamides
  • Codon
  • Enzyme Inhibitors
  • Neoplasm Proteins
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-kit
  • Fusion Proteins, bcr-abl