Kłosowska-Wardęga Agnieszka, Hasumi Yoko, Åhgren Aive, Heldin Carl-Henrik, Hellberg Carina
aLudwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden bDepartment of Dermatology, Faculty of Medicine, University of Yamanashi, Shimokato, Tamaho, Nakakoma, Yamanashi, Japan.
Melanoma Res. 2011 Feb;21(1):57-65. doi: 10.1097/CMR.0b013e32833faf4d.
Melanomas respond poorly to chemotherapy. In this study, we investigated the sensitization of B16 mouse melanoma tumors to paclitaxel by a combination of two tyrosine kinase inhibitors: vatalanib, targeting vascular endothelial growth factor receptors, and imatinib, an inhibitor targeting for example, Abl/BCR-ABL, the platelet-derived growth factor receptor, and stem cell factor receptor c-Kit. C57Bl6/J mice carrying B16/PDGF-BB mouse melanoma tumors were treated daily with vatalanib (25 mg/kg), imatinib (100 mg/kg), or a combination of these drugs. Paclitaxel was given subcutaneously twice during the study. The effects of the drugs on tumor cell proliferation in vitro were determined by counting cells. B16/PDGF-BB mouse melanoma tumors were not sensitive to paclitaxel at doses of either 5 or 20 mg/kg. However, the tumor growth was significantly reduced by 58%, in response to paclitaxel (5 mg/kg) when administered with daily doses of both vatalanib and imatinib. Paclitaxel only inhibited the in-vitro growth of B16/PDGF-BB tumor cells when given in combination with imatinib. Imatinib presumably targets c-Kit, as the cells do not express platelet-derived growth factor receptor and as another c-Abl inhibitor was without effect. This was supported by data from three c-Kit-expressing human melanoma cell lines showing varying sensitization to paclitaxel by the kinase inhibitors. In addition, small interfering RNA knockdown of c-Kit sensitized the cells to paclitaxel. These data show that combination of two tyrosine kinase inhibitors, imatinib and vatalanib, increases the effects of paclitaxel on B16/PDGF-BB tumors, thus suggesting a novel strategy for the treatment of melanomas expressing c-Kit.
黑色素瘤对化疗反应不佳。在本研究中，我们通过联合使用两种酪氨酸激酶抑制剂来研究B16小鼠黑色素瘤肿瘤对紫杉醇的敏感性：凡他尼布，靶向血管内皮生长因子受体；伊马替尼，一种抑制剂，例如靶向Abl/BCR-ABL、血小板衍生生长因子受体和干细胞因子受体c-Kit。携带B16/PDGF-BB小鼠黑色素瘤肿瘤的C57Bl6/J小鼠每天接受凡他尼布（25mg/kg）、伊马替尼（100mg/kg）或这两种药物的联合治疗。在研究期间，紫杉醇皮下注射两次。通过细胞计数来确定药物对体外肿瘤细胞增殖的影响。B16/PDGF-BB小鼠黑色素瘤肿瘤对5mg/kg或20mg/kg剂量的紫杉醇均不敏感。然而，当与凡他尼布和伊马替尼的每日剂量联合给药时，紫杉醇（5mg/kg）使肿瘤生长显著降低了58%。仅当与伊马替尼联合使用时，紫杉醇才会抑制B16/PDGF-BB肿瘤细胞的体外生长。伊马替尼可能靶向c-Kit，因为这些细胞不表达血小板衍生生长因子受体，并且另一种c-Abl抑制剂没有效果。来自三种表达c-Kit的人黑色素瘤细胞系的数据支持了这一点，这些数据显示激酶抑制剂对紫杉醇的敏感性各不相同。此外，c-Kit的小干扰RNA敲低使细胞对紫杉醇敏感。这些数据表明，伊马替尼和凡他尼布这两种酪氨酸激酶抑制剂的联合使用增强了紫杉醇对B16/PDGF-BB肿瘤的作用，从而提示了一种治疗表达c-Kit的黑色素瘤的新策略。
