Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model
Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model
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DOI：
10.1007/s00280-010-1307-z
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发表时间：
2011-01-01
影响因子：
3
通讯作者：
McSheehy, Paul M. J.
中科院分区：
文献类型：
--
作者：
O'Reilly, Terence;Lane, Heidi A.;McSheehy, Paul M. J.
目的依维莫司（RAD 001，Afinitor）是mTORC 1通路抑制剂，瓦他拉尼（PTK/ZK）是泛VEGFR酪氨酸激酶抑制剂（TKI）。这两种药物已被证明具有重叠但也不同的抗血管生成作用。因此，我们研究了药代动力学（PK）和药效学（PD）的组合在vivo.Methods小鼠黑色素瘤B16/BL 6细胞原位生长在BL 6/C57小鼠通过注射到真皮的两个耳朵，建立一个原发性肿瘤，迅速转移到颈部淋巴结。小鼠每天经口给药。PTK/ZK（100 mg/kg）或依维莫司（1 mg/kg）或其组合，并评估抗肿瘤功效（PD）。在同一模型中，血浆PK依维莫司测定单剂量的单药治疗或组合schedures.Results两个独立的实验表明，依维莫司和PTK/ZK的组合导致至少添加剂的抗肿瘤活性增加相比，无论是单一疗法，没有增加毒性。合并数据以提高统计功效，表明相互作用是协同的。PK建模显示，尽管PTK/ZK使依维莫司血浆浓度增加约2倍，但这种PK药物-药物相互作用不能解释联合用药的抗肿瘤作用增加。该模型中PTK/ZK剂量反应曲线的建模表明，依维莫司对PTK/ZK PK的任何影响不太可能影响疗效。测量肿瘤和血浆VEGF水平的变化，在治疗的终点证实了早期观察这两个agents.Conclusions依维莫司和PTK/ZK相结合的差异性影响的治疗人类癌症的承诺。
Purpose Everolimus (RAD001, Afinitor) is an mTORC1 pathway inhibitor, and vatalanib (PTK/ZK) is a pan VEGFR tyrosine kinase inhibitor (TKI). These two drugs have been shown to have overlapping but also distinct anti-angiogenic effects. Consequently, we investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of their combination in vivo.Methods Murine melanoma B16/BL6 cells were grown orthotopically in BL6/C57 mice by injection into the derma of both ears to create a primary tumour which metastasized rapidly to the cervical lymph nodes. Mice were treated daily p.o. with PTK/ZK (100 mg/kg) or everolimus (1 mg/kg) or their combination, and anti-tumour efficacy (PD) assessed. In the same model, plasma PK of everolimus was measured following single doses of the monotherapy or combination schedules.Results Two independent experiments showed that combination of everolimus and PTK/ZK caused at least additive increases in anti-tumour activity compared to either monotherapy, without increases in toxicity. Pooling the data to improve the statistical power demonstrated the interactions to be synergistic. PK modelling showed that although PTK/ZK increased everolimus plasma concentrations by about twofold, this PK drug-drug interaction could not account for the increased anti-tumour effect of the combination. Modelling of the PTK/ZK dose-response curve in this model suggested that any effect of everolimus on the PK of PTK/ZK was unlikely to affect efficacy. Measurement of changes in tumour and plasma VEGF levels at the endpoint of therapy confirmed earlier observations of differential effects of these two agents.Conclusions The combination of everolimus and PTK/ZK hold promise for the treatment of human cancers.