Millennium Pharmaceuticals, Cambridge, MA 02139, USA.
Mol Cancer Ther. 2009 Dec;8(12):3234-43. doi: 10.1158/1535-7163.MCT-09-0239.
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.
了解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开发。硼替佐米是一种首创的蛋白酶体抑制剂，其药代动力学/药效学参数与其疗效的关系尚未得到充分理解。在这里，我们在 CWR22 和 H460 异种移植模型中对硼替佐米的药代动力学/药效学/疗效关系进行了表征。这些研究使我们能够专门解决一个问题，即硼替佐米在实体瘤异种移植模型中缺乏广泛活性是否是由于肿瘤穿透不足所致。体内研究表明，硼替佐米治疗可抑制 CWR22 异种移植瘤的生长，但对 H460 异种移植瘤无效。我们使用 20S 蛋白酶体抑制作为药效学标志物，并分析硼替佐米的肿瘤暴露情况，结果表明，只有在适当的药物暴露驱动蛋白酶体抑制并持续一段时间时，才会产生疗效。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。我们使用动态对比增强磁共振成像和高分辨率计算机断层扫描血管铸型成像，对 CWR22 和 H460 异种移植瘤的血管进行了表征，并确定了血管灌注、通透性和结构的显著差异，这些差异最终导致了硼替佐米在肿瘤中的暴露差异。通过这些技术比较和对比硼替佐米敏感和硼替佐米耐药模型之间的差异，我们建立了肿瘤灌注、药物暴露、药效学反应和疗效之间的关系，并为为什么一些实体瘤模型对硼替佐米治疗没有反应提供了解释。
