Dose-biomarker-response modeling of the anticancer effect of ethaselen in a human non-small cell lung cancer xenograft mouse model  

作　　者：Suo-fu YE Jian LI Shuang-min JI Hui-hui ZENG Wei LU 

机构地区：[1]State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China [2]School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

出　　处：《Acta Pharmacologica Sinica》2017年第2期223-232,共10页中国药理学报（英文版）

基　　金：This work was supported in part by the National Natural Science Foundation （81372266） and the National Science and Technology Major Project, China （2011zx09101-001-03）.

摘　　要：Thioredoxin reductase （TrxR） is a component of several redox-sensitive signaling cascades that mediate important biological processes such as cell survival, maturation, growth, migration and inhibition of apoptosis. The expression levels of TrxR1 in some human carcinoma cell lines are nearly 10 times higher than those in normal cells. Ethaselen is a novel antitumor candidate that exerts potent inhibition on non-small cell lung cancer （NSCLC） by targeting TrxR. In this study we explored the relationship between the ethaselen dose and TrxR activity level and the relationship between TrxR degradation and tumor apoptosis in a human lung carcinoma A549 xenograft model. BALB/c nude mice implanted with human NSCLC cell line A54 were administered ethaselen （36, 72, 108 mg.kg-1.d-1, ig） or vehicle for 10 d. The tumor size and TrxR activity levels in tumor tissues were daily recorded and detected. Based on the. experimental data, NONMEM 7.2 was used to develop an integrated dose-biomarker-response model for describing the quantitative relationship between ethaselen dose and tumor eradication effects. The time course of TrxR activity levels was modeled using an indirect response model （IDR model）, in which the influence of the tumor growth rates on Kin with the linear correction factor γ1 （0.021 d/mm）. The drug binding-inhibition effects on Kout was described using a sigmoidal Emax model with Smax （5.95）, SC50 （136 mg/kg） and Hill＇s coefficient γ2 （2.29）. The influence of TrxR activity inhibition on tumor eradication was characterized by an Emax model with an Emax （130 mm3/d） and EC50 （0.0676）. This model was further validated using a visual predictive check （VPC） and was used to predict the efficacy of different doses. In conclusion, the properties and characteristics of ethaselen acting on TrxR degradation and subsequently resulting in tumor apoptosis are characterized by the IDR model and integrated dose-biomarker-response model with high goodness-of- fit and great predicatThioredoxin reductase （TrxR） is a component of several redox-sensitive signaling cascades that mediate important biological processes such as cell survival, maturation, growth, migration and inhibition of apoptosis. The expression levels of TrxR1 in some human carcinoma cell lines are nearly 10 times higher than those in normal cells. Ethaselen is a novel antitumor candidate that exerts potent inhibition on non-small cell lung cancer （NSCLC） by targeting TrxR. In this study we explored the relationship between the ethaselen dose and TrxR activity level and the relationship between TrxR degradation and tumor apoptosis in a human lung carcinoma A549 xenograft model. BALB/c nude mice implanted with human NSCLC cell line A54 were administered ethaselen （36, 72, 108 mg.kg-1.d-1, ig） or vehicle for 10 d. The tumor size and TrxR activity levels in tumor tissues were daily recorded and detected. Based on the. experimental data, NONMEM 7.2 was used to develop an integrated dose-biomarker-response model for describing the quantitative relationship between ethaselen dose and tumor eradication effects. The time course of TrxR activity levels was modeled using an indirect response model （IDR model）, in which the influence of the tumor growth rates on Kin with the linear correction factor γ1 （0.021 d/mm）. The drug binding-inhibition effects on Kout was described using a sigmoidal Emax model with Smax （5.95）, SC50 （136 mg/kg） and Hill＇s coefficient γ2 （2.29）. The influence of TrxR activity inhibition on tumor eradication was characterized by an Emax model with an Emax （130 mm3/d） and EC50 （0.0676）. This model was further validated using a visual predictive check （VPC） and was used to predict the efficacy of different doses. In conclusion, the properties and characteristics of ethaselen acting on TrxR degradation and subsequently resulting in tumor apoptosis are characterized by the IDR model and integrated dose-biomarker-response model with high goodness-of- fit and great predicat

关 键 词：non-small cell lung cancer （NSCLC） thioredoxin reductase anticancer drug ETHASELEN dose-biomarker-response model NONMEM 

分 类 号：Q279[生物学—细胞生物学] S852.43[农业科学—基础兽医学]