Hicks Kevin O, Myint Hilary, Patterson Adam V, Pruijn Frederik B, Siim Bronwyn G, Patel Kashyap, Wilson William R
Auckland Cancer Society Research Centre, University of Auckland School of Medical Sciences, Auckland, New Zealand.
Int J Radiat Oncol Biol Phys. 2007 Oct 1;69(2):560-71. doi: 10.1016/j.ijrobp.2007.05.049.
To compare oxygen dependence and tissue transport properties of a new hypoxia-activated prodrug, PR-104A, with tirapazamine, and to evaluate the implications for antitumor activity when combined with radiotherapy.
Oxygen dependence of cytotoxicity was measured by clonogenic assay in SiHa cell suspensions. Tissue transport parameters were determined using SiHa multicellular layers. Spatially resolved pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to predict cell killing in SiHa tumors and tested by clonogenic assay 18 h after treatment with the corresponding phosphate ester, PR-104.
The K-value (oxygen concentration to halve cytotoxic potency) of PR-104A was 0.126 +/- 0.021 microM (10-fold lower than tirapazamine at 1.30 +/- 0.28 microM). The diffusion coefficient of PR-104A in multicellular layers (4.42 +/- 0.15 x 10(-7) cm2 s(-1)) was lower than that of tirapazamine (1.30 +/- 0.05 x 10(-6) cm2 s(-1)) but PK modeling predicted better penetration to hypoxic cells in tumors because of its slower metabolism. The tirapazamine PK/PD model successfully predicted the measured activity in combination with single-dose radiation against SiHa tumors, and the PR-104A model underpredicted the activity, which was greater for PR-104 than for tirapazamine (at equivalent host toxicity) both with radiation and as a single agent.
PR-104/PR-104A has different PK/PD properties from tirapazamine and superior activity with single-dose radiotherapy against SiHa xenografts. We have inferred that PR-104A is better able to kill cells at intermediate partial pressure of oxygen in tumors than implied by the PK/PD model, most likely because of a bystander effect resulting from diffusion of its activated metabolites from severely hypoxic zones.
比较新型低氧激活前药PR - 104A与替拉扎明的氧依赖性和组织转运特性，并评估其与放疗联合应用时对抗肿瘤活性的影响。
通过克隆形成试验在SiHa细胞悬液中测量细胞毒性的氧依赖性。使用SiHa多细胞层测定组织转运参数。建立空间分辨药代动力学（PK）和药效动力学（PD）模型以预测SiHa肿瘤中的细胞杀伤情况，并在用相应的磷酸酯PR - 104处理18小时后通过克隆形成试验进行测试。
PR - 104A的K值（使细胞毒性效力减半的氧浓度）为0.126±0.021微摩尔（比替拉扎明的1.30±0.28微摩尔低10倍）。PR - 104A在多细胞层中的扩散系数（4.42±0.15×10⁻⁷平方厘米·秒⁻¹）低于替拉扎明（1.30±0.05×10⁻⁶平方厘米·秒⁻¹），但PK模型预测其在肿瘤中对低氧细胞的穿透性更好，因为其代谢较慢。替拉扎明的PK/PD模型成功预测了与单剂量放疗联合应用时对SiHa肿瘤的实测活性，而PR - 104A模型低估了活性，在放疗和单药治疗时，PR - 104在同等宿主毒性下的活性均高于替拉扎明。
PR - 104/PR - 104A具有与替拉扎明不同的PK/PD特性，在对SiHa异种移植瘤的单剂量放疗中具有更强的活性。我们推测，PR - 104A在肿瘤中氧分压处于中等水平时比PK/PD模型所暗示的更能有效杀伤细胞，这很可能是由于其活化代谢产物从严重低氧区域扩散产生的旁观者效应。
