Synergistic antiproliferative effects of KIT tyrosine kinase inhibitors on neoplastic canine mast cells

• Published in: Experimental hematology Vol. 35; no. 10; pp. 1510 - 1521
• Main Authors: Gleixner, Karoline V., Rebuzzi, Laura, Mayerhofer, Matthias, Gruze, Alexander, Hadzijusufovic, Emir, Sonneck, Karoline, Vales, Anja, Kneidinger, Michael, Samorapoompichit, Puchit, Thaiwong, Tuddow, Pickl, Winfried F., Yuzbasiyan-Gurkan, Vilma, Sillaber, Christian, Willmann, Michael, Valent, Peter
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.10.2007
• Subjects: Advanced Basic Science; Animals; Apoptosis - drug effects; Cell Cycle - drug effects; Cell Line, Tumor; Dog Diseases - drug therapy; Dog Diseases - metabolism; Dogs; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Drug Synergism; Hematologic Neoplasms - drug therapy; Hematologic Neoplasms - metabolism; Hematologic Neoplasms - pathology; Hematologic Neoplasms - veterinary; Hematology, Oncology, and Palliative Medicine; Humans; Mast Cells - metabolism; Mast Cells - pathology; Mast-Cell Sarcoma - drug therapy; Mast-Cell Sarcoma - metabolism; Mast-Cell Sarcoma - pathology; Mast-Cell Sarcoma - veterinary; Protein Kinase Inhibitors - agonists; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-kit - metabolism
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2007.06.005

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 3H-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.