Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program
Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program
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DOI：
10.1002/pbc.21535
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发表时间：
2008-07-01
影响因子：
3.2
通讯作者：
Smith, Malcolm A.
中科院分区：
文献类型：
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作者：
Maris, John M.;Courtright, Joshua;Smith, Malcolm A.
背景。舒尼替尼是一种口服生物可利用的多靶点酪氨酸激酶抑制剂，对 PDGF 受体、VEGF 受体、FLT3 和 KIT 具有选择性。程序。舒尼替尼在 0.1 nM 至 1.0 muM 的浓度范围内针对来自 PPTP 体外组的 23 种细胞系进行了测试。我们还在代表 9 种不同儿科癌症组织学的 46 个小鼠异种移植模型中比较了通过口服强饲法给予舒尼替尼 (53.5 mg/kg) 或载体的 28 个粘土。结果。白血病细胞系 Kasumi-1（功能获得性 KITAsn822Lys 突变）是唯一对舒尼替尼具有体外反应的细胞系（IC50 75.7 nM）。舒尼替尼显着延长了 35 个实体瘤中的 19 个（54%）的 EFS，以及所分析的 8 个 ALL 异种移植物中的 3 个（38%）的 EFS。使用 PPTP 疗效时间测量，舒尼替尼对 34 个可评估实体瘤异种移植物中的 14 个具有中度 (13) 和高 (1) 水平的活性，其中包括 6 个横纹肌肉瘤中的 4 个、5 个尤因特纳瘤中的 4 个和 3 个横纹肌样瘤异种移植物中的 2 个。在第 28 天停止治疗 14 个没有发生肿瘤事件的实体瘤异种移植物后，大多数肿瘤生长速度增加。在实体瘤组中，舒尼替尼唯一出现的衰退是横纹肌样瘤异种移植物的完全缓解。结论。舒尼替尼对大多数 PPTP 实体瘤组表现出显着的肿瘤生长抑制作用，但对神经母细胞瘤和 ALL 组的活性很少。抗肿瘤活性主要表现为肿瘤生长延迟，这与舒尼替尼针对许多评估的儿科临床前模型的抗血管生成作用一致。
Background. Sunitinib is an orally bioavailable, multi-targeted tyrosine kinase inhibitor with selectivity for PDGF receptors, VEGF receptors, FLT3, and KIT. Procedures. Sunitinib was tested at concentrations ranging from 0.1 nM to 1.0 mu M against 23 cell lines from the PPTP in vitro panel. We also compared sunitinib (53.5 mg/kg) or vehicle administered for 28 clays by oral gavage in 46 murine xenograft models representing 9 distinct pediatric cancer histologies. Results. The leukemia cell line, Kasumi-1 (gain-of-function KITAsn822Lys mutation) was the only line with an in vitro response to sunitinib (IC50 75.7 nM). Sunitinib significantly prolonged EFS in 19 of 35 (54%) of the solid tumor, and in 3 of 8 (38%) of the ALL xenografts analyzed. Using the PPTP time to event measure of efficacy, sunitinib had intermediate (13) and high (1) levels of activity against 14 of 34 evaluable solid tumor xenografts, including 4 of 6 rhabdomyosarcoma, 4 of 5 Ewing turner, and 2 of 3 rhabdoid tumor xenografts. Following cessation of treatment for the 14 solid tumor xenografts without tumor events by day 28, tumor growth rate increased in most. The only regression noted to sunitinib in the solid tumor panels was a complete response in a rhabdoid tumor xenograft. Conclusions. Sunitinib demonstrated significant tumor growth inhibition against most of the PPTP's solid tumor panels, but little activity against the neuroblastoma and ALL panel. Antitumor activity was manifested primarily as tumor growth delay, consistent with an anti-angiogenic effect for sunitinib against many of the pediatric preclinical models evaluated.