Utilization of quantitative in vivo pharmacology approaches to assess combination effects of everolimus and irinotecan in mouse xenograft models of colorectal cancer.
Utilization of quantitative in vivo pharmacology approaches to assess combination effects of everolimus and irinotecan in mouse xenograft models of colorectal cancer.
复制标题
DOI：
10.1371/journal.pone.0058089
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Weekes CD
中科院分区：
文献类型：
--
作者：
Bradshaw-Pierce EL;Pitts TM;Kulikowski G;Selby H;Merz AL;Gustafson DL;Serkova NJ;Eckhardt SG;Weekes CD
PI 3 K/AKT/mTOR通路在癌症中经常失调，并且mTOR的抑制已经证明了调节促存活通路的能力。因此，我们试图确定mTOR抑制剂依维莫司增强伊立替康在结直肠癌（CRC）中的抗肿瘤作用的能力。在体外和体内评价了依维莫司和伊立替康在携带PIK 3CA、KRAS和/或BRAF常见突变的CRC细胞系中的联合作用。建立了依维莫司和伊立替康的药代动力学定向给药方案，并用于评估药物的体内抗肿瘤作用。在治疗结束时，每个治疗组收获3-6个肿瘤用于通过NMR代谢组学进行生物标志物分析。依维莫司和伊立替康/SN 38在体外多种CRC细胞系中显示出协同抗增殖作用。使用临床相关给药方案，在CRC异种移植模型中测定依维莫司和伊立替康的联合作用。在HT 29和HCT 116肿瘤异种移植物中，依维莫司单独给药和与伊立替康联合给药时显示出显著的肿瘤生长抑制作用。代谢组学分析表明，HT 29肿瘤比HCT 116肿瘤更具有代谢反应性。依维莫司导致两种肿瘤类型的糖酵解减少，而伊立替康治疗导致HT 29肿瘤中脂质大量蓄积，表明具有细胞毒性作用。肿瘤生长和代谢组学数据的定量分析显示，依维莫司和伊立替康的组合在BRAF/PIK 3CA突变体HT 29肿瘤异种移植物中比在KRAS/PIK 3CA突变体HCT 116肿瘤异种移植物中更有益，BRAF/PIK 3CA突变体HT 29肿瘤异种移植物具有累加效应，KRAS/PIK 3CA突变体HCT 116肿瘤异种移植物具有小于累加效应。
The PI3K/AKT/mTOR pathway is frequently dysregulated in cancers and inhibition of mTOR has demonstrated the ability to modulate pro-survival pathways. As such, we sought to determine the ability of the mTOR inhibitor everolimus to potentiate the antitumor effects of irinotecan in colorectal cancer (CRC). The combinatorial effects of everolimus and irinotecan were evaluated in vitro and in vivo in CRC cell lines harboring commonly found mutations in PIK3CA, KRAS and/or BRAF. Pharmacokinetically-directed dosing protocols of everolimus and irinotecan were established and used to assess the in vivo antitumor effects of the agents. At the end of treatment, 3–6 tumors per treatment arm were harvested for biomarker analysis by NMR metabolomics. Everolimus and irinotecan/SN38 demonstrated synergistic anti-proliferative effects in multiple CRC cell lines in vitro. Combination effects of everolimus and irinotecan were determined in CRC xenograft models using clinically-relevant dosing protocols. Everolimus demonstrated significant tumor growth inhibition alone and when combined with irinotecan in HT29 and HCT116 tumor xenografts. Metabolomic analysis showed that HT29 tumors were more metabolically responsive than HCT116 tumors. Everolimus caused a decrease in glycolysis in both tumor types whilst irinotecan treatment resulted in a profound accumulation of lipids in HT29 tumors indicating a cytotoxic effect. Quantitative analysis of tumor growth and metabolomic data showed that the combination of everolimus and irinotecan was more beneficial in the BRAF/PIK3CA mutant HT29 tumor xenografts, which had an additive effect, than the KRAS/PIK3CA mutant HCT116 tumor xenografts, which had a less than additive effect.
登录
查看更多内容
影响因子：
4.1
作者：
Klawitter, Jelena;Gottschalk, Sven;Hainz, Carsten;Leibfritz, Dieter;Christians, Uwe;Serkova, Natalie J.
通讯作者：
Serkova, Natalie J.
DOI：
10.1158/1078-0432.ccr-09-1314
发表时间：
2010-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Houghton PJ
通讯作者：
Houghton PJ
影响因子：
45.3
作者：
Giantonio, Bruce J.;Catalano, Paul J.;Benson, Al B., III
通讯作者：
Benson, Al B., III
影响因子：
4.8
作者：
Gera, JF;Mellinghoff, IK;Lichtenstein, AK
通讯作者：
Lichtenstein, AK
影响因子：
45.3
作者：
O'Donnell, Anne;Faivre, Sandrine;Judson, Ian
通讯作者：
Judson, Ian