Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model.
Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model.
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DOI：
10.1002/ijc.24606
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发表时间：
2009-12-01
影响因子：
6.4
通讯作者：
Raschellà G
中科院分区：
文献类型：
--
作者：
Vitali R;Mancini C;Cesi V;Tanno B;Piscitelli M;Mancuso M;Sesti F;Pasquali E;Calabretta B;Dominici C;Raschellà G
4期神经母细胞瘤(NB)是一种毁灭性的儿童癌症，其不良预后在过去20年中基本没有改变。受体酪氨酸激酶在调控NB细胞的增殖、分化和凋亡过程中发挥着重要作用。因此，我们在体外和小鼠原位模型中测试了第二代酪氨酸激酶抑制剂Dasatinib在人NB细胞系中的活性。达沙替尼对10个受试细胞系中7个细胞系的IC50在亚微摩尔范围内具有抑制作用。在敏感细胞中，Dasatinib减少了非锚定生长，在某些情况下，还诱导了衰老和凋亡。在HTLA-230细胞中，达沙替尼可下调c-Kit和c-Src的磷酸化，并强烈抑制ERK1/2和Akt的活性。为了验证达沙替尼在体内的疗效，将HTLA-230和SY5Y细胞原位注射到裸鼠肾上腺内，药物治疗一直持续到第40天。在注射HTLA-230细胞的小鼠中，在注射后7天开始治疗时，每天30 mg/kg的剂量显著抑制肿瘤的生长。在注射体外高度敏感的SY5Y细胞(IC50=92 nM)的动物中，达沙替尼60 mg/kg/d的抗肿瘤作用仅在注射后1天开始。然而，达沙替尼在体内的抗肿瘤作用在两种原位模型中都是部分的，强调了在接近模拟人类肿瘤的动物环境中测试候选新药的重要性。
Stage 4 neuroblastoma (NB) is a devastating childhood cancer whose poor outcome has remained essentially unchanged in the last 20 years. Receptor tyrosine kinases have important roles in the control of proliferation, differentiation and apoptosis of NB cells. Thus, we tested the activity of second generation tyrosine kinase inhibitor Dasatinib in human NB cell lines in vitro and in an orthotopic mouse model. Dasatinib inhibited cell viability with an IC50 in the submicromolar range in 7 of 10 tested cell lines. In sensitive cells, Dasatinib reduced anchorage-independent growth and, in some instances, induced senescence and apoptosis. In HTLA-230 cells, Dasatinib treatment caused down-regulation of c-Kit and c-Src phosphorylation in conjunction with strong inhibition of Erk1/2 and Akt activity. To test the efficacy of Dasatinib in vivo, HTLA-230 and SY5Y cells were orthotopically injected in the adrenal gland of nude mice and drug treatments carried out until day 40. In mice injected with HTLA-230 cells, tumour growth was significantly inhibited at the dose of 30 mg/Kg/day when treatment was started 7 days after injection. In animals injected with SY5Y cells that were exquisitely sensitive in vitro (IC50= 92 nM), the antitumour effect of Dasatinib was observed at the dose of 60mg/Kg/day but only when treatment was started 1 day after injection. However, the anti-tumour effect of Dasatinib in vivo was partial in both orthotopic models, emphasizing the importance of testing candidate new drugs in animal environments closely mimicking the human tumour.
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DOI：
10.1073/pnas.92.20.9363
发表时间：
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影响因子：
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