由儿科临床前测试计划对苏尼替尼进行初步测试(第1阶段)。

PubMed ID
发表日期 2008年Jul月

原始出处 小儿血液与癌症
Pediatric blood & cancer
作者 Maris  John M  Courtright  Joshua  Houghton  Peter J  Morton  Christopher L  Kolb  E Anders  Lock  Richard  Tajbakhsh  Mayamin  Reynolds  C Patrick  Keir  Stephen T  Wu  Jianrong  Smith  Malcolm A 

文献标题 由儿科临床前测试计划对苏尼替尼进行初步测试(第1阶段)。
Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program.

文献摘要 BACKGROUND

苏尼替尼是一种口服生物利用的多靶向酪氨酸激酶抑制剂,对PDGF受体、VEGF受体、FLT3和KIT具有选择性。

PROCEDURES

Sunitinib在0.1nm到1.0微米的浓度范围内对来自PPTP体外培养板的23个细胞系进行了测试。我们还比较了苏尼替尼(53.5mg/kg)或口服灌胃给药28天的载体在46个异种小鼠模型中的应用,这些模型代表了9种不同的儿童癌症组织学。

RESULTS

白血病细胞系Kasumi-1(gain of function KIT(Asn822Lys)突变)是唯一对sunitinib(IC(50)75.7nm)有体外应答的细胞系。在35例实体瘤中有19例(54%)和8例(38%)异种移植瘤中有3例(38%)Sunitinib显著延长EFS。采用PPTP时间-事件效应法,舒尼替尼对34例可评价的实体瘤移植瘤中的14例(包括6例横纹肌肉瘤中的4例、5例尤文瘤中的4例和3例横纹肌瘤移植瘤中的2例)具有中等(13)和高(1)的活性。到第28天,14个无肿瘤事件的实体瘤异种移植瘤停止治疗后,大多数肿瘤生长率增加。苏尼替尼在实体瘤中的唯一消退是在横纹肌样肿瘤异种移植中的完全反应。

CONCLUSIONS

苏尼替尼对大部分PPTP实体瘤细胞有明显的抑瘤作用,但对神经母细胞瘤和全细胞瘤细胞无明显的抑瘤作用。抗肿瘤活性主要表现为肿瘤生长延迟,这与sunitinib对许多儿科临床前模型的抗血管生成作用一致。儿科血癌2008;51:42-48。(c) 2008威利利斯公司。


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 microM against 23 cell lines from the PPTP in vitro panel. We also compared sunitinib (53.5 mg/kg) or vehicle administered for 28 days by oral gavage in 46 murine xenograft models representing 9 distinct pediatric cancer histologies.

RESULTS

The leukemia cell line, Kasumi-1 (gain-of-function KIT(Asn822Lys) mutation) was the only line with an in vitro response to sunitinib (IC(50) 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 tumor, 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. Pediatr Blood Cancer 2008;51:42-48. (c) 2008 Wiley-Liss, Inc.


获取全文 10.1002/pbc.21535