Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs
Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs
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DOI：
10.1093/jnci/djj306
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发表时间：
2006-08-16
影响因子：
10.3
通讯作者：
Wilson, William R.
中科院分区：
文献类型：
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作者：
Hicks, Kevin O.;Pruijn, Frederik B.;Wilson, William R.
背景由于实体瘤的脉管系统效率低下，抗癌药物必须通过血管外隔室穿透相对长的距离。对这种扩散的要求可能会限制它们的活性，特别是低氧靶向药物的活性。我们测试了基于代表性映射肿瘤微血管网络的三维药代动力学/药效学（PK/PD）模型是否可以预测抗癌药物在小鼠异种移植肿瘤中的治疗活性。研究方法：低氧激活的抗癌药物替拉扎明（TPZ）和15 TPZ类似物的扩散系数估计通过测量其运输通过HT 29结肠癌多细胞层（MCL）。在HT 29细胞悬液中测量TPZ类似物的厌食症细胞毒性效力（通过克隆形成测定）和代谢，并在CD-1裸鼠中测量其血浆药代动力学。该信息用于创建肿瘤微血管网络的空间分辨PK/PD模型。将模型预测与实际低氧细胞杀伤进行比较，如在用每种TPZ类似物处理后18小时通过对HT 29异种移植肿瘤的克隆形成测定所测量的。结果如下：模拟TPZ在肿瘤微血管网络中的运输显示，在大多数缺氧区域中药物消耗显著，预测的最大细胞杀伤仅为3个对数，而如果没有运输障碍，则超过10个对数。观察到TPZ类似物的组织扩散系数范围较大（0.027 × 10（-6）-1.87 × 10（-6）cm（2）/s）。模型预测和测量的低氧细胞杀伤之间存在强相关性（R-2=0.89），但当模型不包括血管外转运时相关性较差（R-2=0.32）。结论：肿瘤中的血管外转运及其对肿瘤细胞杀伤的后果可以通过测量药物在体外通过MCL的渗透并在三维微血管网络中的每个位置建模药代动力学来预测。
Background. Because of the inefficient vasculature of solid tumors, anticancer drugs must penetrate relatively long distances through the extravascular compartment. The requirement for such diffusion may limit their activity, especially that of hypoxia-targeted drugs. We tested whether a three-dimensional pharmacokinetic/pharmacodynamic (PK/PD) model based on a representative mapped tumor microvascular network could predict the therapeutic activity of anticancer drugs in mouse xenograft tumors. Methods: Diffusion coefficients of the hypoxia-activated anticancer drug tirapazamine (TPZ) and of 15 TPZ analogs were estimated by measuring their transport through HT29 colon cancer multicellular layers (MCLs). Anoxic cytotoxic potency (by clonogenic assay) and metabolism of the TPZ analogs were measured in HT29 cell suspensions, and their plasma pharmacokinetics was measured in CD-1 nude mice. This information was used to create a spatially resolved PK/PD model for the tumor microvascular network. Model predictions were compared with actual hypoxic cell kill as measured by clonogenic assays on HT29 xenograft tumors 18 hours after treatment with each TPZ analog. Results: Modeling TPZ transport in the tumor microvascular network showed substantial drug depletion in the most hypoxic regions, with predicted maximum cell kill of only 3 logs, compared with more than 10 logs if there were no transport impediment. A large range of tissue diffusion coefficients (0.027x10(-6)-1.87x10(-6) cm(2)/s) was observed for the TPZ analogs. There was a strong correlation between model-predicted and measured hypoxic cell kill (R-2=0.89) but a poor correlation when the model did not include extravascular transport (R-2=0.32). Conclusions: Extravascular transport in tumors, and its consequences for tumor cell killing, can be predicted by measuring drug penetration through MCLs in vitro and modeling pharmacokinetics at each position in three-dimensional microvascular networks.