The relationship among tumor architecture, pharmacokinetics, pharmacodynamics, and efficacy of bortezomib in mouse xenograft models
The relationship among tumor architecture, pharmacokinetics, pharmacodynamics, and efficacy of bortezomib in mouse xenograft models
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DOI：
10.1158/1535-7163.mct-09-0239
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发表时间：
2009-12-01
影响因子：
5.7
通讯作者：
Kupperman, Erik
中科院分区：
文献类型：
--
作者：
Williamson, Mark J.;Silva, Matthew D.;Kupperman, Erik
了解一种化合物的临床前药代动力学、药效学和疗效关系，可以极大地促进其临床发展。Bortezomib是一种一流的蛋白酶体抑制剂，其药代动力学/药效学参数与疗效的关系尚不清楚。在CWR22和H460异种移植模型中，我们研究了Bortezomib的药代动力学/药效学/药效关系。这些研究使我们能够具体解决实体瘤移植中缺乏广泛的Bortezomib活性是否由于肿瘤穿透不足的问题。体内研究表明，硼替佐米治疗可抑制CWR22移植瘤的生长，但不能抑制H460移植瘤的生长。以20S蛋白酶体抑制作为药效学指标，并分析Bortezomib肿瘤暴露，我们表明，只有当适当的药物暴露推动蛋白酶体抑制并随着时间的推移而持续时，才能达到疗效。这表明蛋白酶体抑制的幅度和持续时间都是疗效的重要驱动因素。使用动态增强磁共振成像和高分辨率CT血管铸型成像，我们表征了CWR22和H460异种移植瘤的血管系统，并确定了血管灌注量、渗透性和结构方面的显著差异，这些差异最终导致了Bortezomib肿瘤暴露的差异。通过使用这些技术比较和对比Bortezomib敏感和耐药模型之间的差异，我们可以建立肿瘤灌注、药物暴露、药效反应和疗效之间的关系，并解释为什么一些实体肿瘤模型对Bortezomib治疗没有反应。[摩尔癌症治疗2009；8(12)：3234-43]
Understanding a compound's preclinical pharmacokinetic, pharmacodynamic, and efficacy relationship can greatly facilitate its clinical development. Bortezomib is a first-in-class proteasome inhibitor whose pharmacokinetic/pharmacodynamic parameters are poorly understood in terms of their relationship with efficacy. Here we characterized the bortezomib pharmacokinetic/pharmacodynamic/efficacy relationship in the CWR22 and H460 xenograft models. These studies allowed us to specifically address the question of whether the lack of broad bortezomib activity in solid tumor xenografts was due to insufficient tumor penetration. In vivo studies showed that bortezomib treatment resulted in tumor growth inhibition in CWR22 xenografts, but not in H460 xenografts. Using 20S proteasome inhibition as a pharmacodynamic marker and analyzing bortezomib tumor exposures, we show that efficacy was achieved only when suitable drug exposures drove proteasome inhibition that was sustained over time. This suggested that both the magnitude and duration of proteasome inhibition were important drivers of efficacy. Using dynamic contrast-enhanced magnetic resonance imaging and high-resolution computed tomographic imaging of vascular casts, we characterized the vasculature of CWR22 and H460 xenograft tumors and identified prominent differences in vessel perfusion, permeability, and architecture that ultimately resulted in variations in bortezomib tumor exposure. Comparing and contrasting the differences between a bortezomib-responsive and a bortezomib-resistant model with these techniques allowed us to establish a relationship among tumor perfusion, drug exposure, pharmacodynamic response and efficacy, and provided an explanation for why some solid tumor models do not respond to bortezomib treatment. [Mol Cancer Ther 2009;8(12):3234-43]