Synergistic antiproliferative effects of KIT tyrosine kinase inhibitors on neoplastic canine mast cells.
Aggressive mast cell (MC) tumors are hematopoietic neoplasms characterized by uncontrolled growth of MC and resistance to conventional drugs. In most cases, the tyrosine kinase (TK) receptor KIT is involved in malignant cell growth. Therefore, several KIT TK-targeting drugs are currently being tested for their ability to block growth of neoplastic MC. We examined the effects of four TK inhibitors (imatinib, midostaurin, nilotinib, and dasatinib) on C2 canine mastocytoma cells, as well as primary neoplastic canine MC. As assessed by (3)H-thymidine incorporation experiments, all TK inhibitors produced dose-dependent inhibition of proliferation in C2 cells with the following IC(50) values: imatinib: 269 +/- 180 nM, midostaurin: 157 +/- 35 nM, nilotinib: 55 +/- 24 nM, dasatinib: 12 +/- 3 nM. Growth-inhibitory effects of TK inhibitors were also observed in primary neoplastic mast cells, although IC(50) values for each drug varied from patient to patient, with midostaurin being the most potent agent in all samples tested. In consecutive experiments, we were able to show that TK inhibitors cooperate with each other in producing growth inhibition in C2 cells with synergistic effects observed with most drug combinations. In flow cytometry and TUNEL assay experiments, growth-inhibitory effects of TK inhibitors were found to be associated with cell-cycle arrest and apoptosis. Together, these data show that several TK-targeting drugs induce apoptosis and inhibit proliferation in canine mastocytoma cells in vitro, and that synergistic drug interactions can be obtained. Clinical trials are now warranted to explore whether these TK inhibitors also counteract growth of neoplastic cells in vivo in patients with aggressive MC tumors.
Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
Karoline V
KV
Gleixner
Laura
L
Rebuzzi
Matthias
M
Mayerhofer
Alexander
A
Gruze
Emir
E
Hadzijusufovic
Karoline
K
Sonneck
Anja
A
Vales
Michael
M
Kneidinger
Puchit
P
Samorapoompichit
Tuddow
T
Thaiwong
Winfried F
WF
Pickl
Vilma
V
Yuzbasiyan-Gurkan
Christian
C
Sillaber
Michael
M
Willmann
Peter
P
Valent
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004283:Dog Diseases / Q000188:drug therapy* / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000662:veterinary*; D006801:Humans; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D012515:Mast-Cell Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000662:veterinary*; D047428:Protein Kinase Inhibitors / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit