Synergistic antiproliferative effects of KIT tyrosine kinase inhibitors on neoplastic canine mast cells
Synergistic antiproliferative effects of KIT tyrosine kinase inhibitors on neoplastic canine mast cells
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DOI：
10.1016/j.exphem.2007.06.005
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发表时间：
2007-10-01
影响因子：
2.6
通讯作者：
Valent, Peter
中科院分区：
文献类型：
--
作者：
Gleixner, Karoline V.;Rebuzzi, Laura;Valent, Peter
侵袭性肥大细胞 (MC) 肿瘤是一种造血系统肿瘤，其特征是 MC 生长失控和对常规药物产生耐药性。在大多数情况下，酪氨酸激酶 (TK) 受体 KIT 参与恶性细胞生长。因此，目前正在测试几种 KIT TK 靶向药物阻止肿瘤性 MC 生长的能力。我们检查了四种 TK 抑制剂（伊马替尼、米斯托林、尼罗替尼和达沙替尼）对 C2 犬肥大细胞瘤细胞以及原发性肿瘤犬 MC 的影响。通过 H-3-胸苷掺入实验评估，所有 TK 抑制剂均对 C2 细胞产生剂量依赖性增殖抑制，IC50 值如下：伊马替尼：269 +/- 180 nM，米斯托林：157 +/- 35 nM，尼洛替尼：55 +/- 24 nM，达沙替尼：12 +/- 3 nM。在原发性肿瘤肥大细胞中也观察到了 TK 抑制剂的生长抑制作用，尽管每种药物的 IC50 值因患者而异，其中米多斯托林是所有测试样品中最有效的药物。在连续的实验中，我们能够证明 TK 抑制剂相互配合，在 C2 细胞中产生生长抑制作用，并且在大多数药物组合中观察到协同效应。在流式细胞术和 TUNEL 测定实验中，发现 TK 抑制剂的生长抑制作用与细胞周期停滞和细胞凋亡有关。总之，这些数据表明，几种 TK 靶向药物在体外诱导犬肥大细胞瘤细胞凋亡并抑制增殖，并且可以获得协同药物相互作用。现在有必要进行临床试验来探索这些 TK 抑制剂是否也能抑制侵袭性 MC 肿瘤患者体内肿瘤细胞的生长。 (c) 2007 年 ISEH-血液学和干细胞学会。由爱思唯尔公司出版
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 H-3-thymidine incorporation experiments, all TK inhibitors produced dose-dependent inhibition of proliferation in C2 cells with the following IC50 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 IC50 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. (c) 2007 ISEH-Society for Hematology and Stem Cells. Published by Elsevier Inc.