Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-β kinase antagonist, in mice
Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-β kinase antagonist, in mice
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DOI：
10.1016/j.ejca.2007.10.008
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发表时间：
2008-01-01
影响因子：
8.4
通讯作者：
Troconiz, Inaki F.
中科院分区：
文献类型：
--
作者：
Bueno, Lorea;de Alwis, Dinesh P.;Troconiz, Inaki F.
将人异种移植物Calu 6（非小细胞肺癌）和MX 1（乳腺癌）皮下植入裸鼠中，并口服给予新型I型受体TGF-β激酶拮抗剂LY 2157299。以LY 2157299的血药浓度、肿瘤中磷酸化Smad 2，3（pSmad）的百分比和肿瘤大小为指标，建立半机械药代动力学/药效学模型，以间接反应模型将血药浓度与pSmad联系起来。该模型预测pSmad的完全抑制和快速转换率[t（1/2）（min）= 18.6（Calu 6）和32.0（MX 1）]。使用两个信号转导隔室将肿瘤生长抑制与pSmad联系起来，其特征在于Calu 6和MX 1的平均信号传播时间估计值分别为6.17和28.7天。该模型提供了一种工具来产生实验假设，以深入了解与I型TGF-β膜受体相关的信号转导机制。(C)2007爱思唯尔有限公司保留所有权利。
Human xenografts Calu6 (non-small cell lung cancer) and MX1 (breast cancer) were implanted subcutaneously in nude mice and LY2157299, a new type I receptor TGF-beta kinase antagonist, was administered orally. Plasma levels of LY2157299, percentage of phosphorylated Smad2,3 (pSmad) in tumour, and tumour size were used to establish a semi-mechanistic pharmacokinetic/pharmacodynamic model.An indirect response model was used to relate plasma concentrations with pSmad. The model predicts complete inhibition of pSmad and rapid turnover rates [t(1/2) (min) = 18.6 (Calu6) and 32.0 (MX1)]. Tumour growth inhibition was linked to pSmad using two signal transduction compartments characterised by a mean signal propagation time with estimated values of 6.17 and 28.7 days for Calu6 and MX1, respectively.The model provides a tool to generate experimental hypothesis to gain insights into the mechanisms of signal transduction associated to the TGF-beta membrane receptor type I. (C) 2007 Elsevier Ltd. All rights reserved.