Abstract:
Hypoxia-activated prodrugs are bioactivated in oxygen-deficient tumour regions and represent a novel strategy to exploit this pharmacological sanctuary for therapeutic gain. The approach relies on the selective metabolism of the prodrug under pathological hypoxia to generate active metabolites with the potential to diffuse throughout the tumour microenvironment and potentiate cell killing by means of a \"bystander effect\". In the present study, we investigate the pharmacological properties of the nitrogen mustard prodrug CP-506 in tumour tissues using in silico spatially-resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) modelling. The approach employs a number of experimental model systems to define parameters for the cellular uptake, metabolism and diffusion of both the prodrug and its metabolites. The model predicts rapid uptake of CP-506 to high intracellular concentrations with its long plasma half-life driving tissue diffusion to a penetration depth of 190 µm, deep within hypoxic activating regions. While bioreductive metabolism is restricted to regions of severe pathological hypoxia (<1 µM O2), its active metabolites show substantial bystander potential with release from the cell of origin into the extracellular space. Model predictions of bystander efficiency were validated using spheroid co-cultures, where the clonogenic killing of metabolically defective \"target\" cells increased with the proportion of metabolically competent \"activator\" cells. Our simulations predict a striking bystander efficiency at tissue-like densities with the bis-chloro-mustard amine metabolite (CP-506M-Cl2) identified as a major diffusible metabolite. Overall, this study shows that CP-506 has favourable pharmacological properties in tumour tissue and supports its ongoing development for use in the treatment of patients with advanced solid malignancies.
摘要:
缺氧激活的前药在缺氧的肿瘤区域被生物激活,代表了一种利用这种药理保护区获得治疗收益的新策略。该方法依赖于前药在病理性缺氧下的选择性代谢,以产生具有扩散到整个肿瘤微环境并通过“旁观者效应”增强细胞杀伤能力的活性代谢物。在本研究中,我们使用计算机空间分辨的药代动力学/药效学(SR-PK/PD)模型研究了氮芥前药CP-506在肿瘤组织中的药理特性。该方法采用了许多实验模型系统来定义细胞摄取的参数,前药及其代谢物的代谢和扩散。该模型预测CP-506的快速摄取到高细胞内浓度,其长血浆半衰期驱动组织扩散到190µm的穿透深度,在低氧激活区域的深处。虽然生物还原性代谢仅限于严重病理性缺氧(<1µMO2)的区域,它的活性代谢物显示出相当大的旁观者潜力,从起源细胞释放到细胞外空间。使用球体共培养验证了旁观者效率的模型预测,其中代谢缺陷的“目标”细胞的克隆杀伤作用随着代谢能力的“激活剂”细胞的比例而增加。我们的模拟预测,在组织样密度下,双氯芥子气胺代谢物(CP-506M-Cl2)被确定为主要的扩散代谢物,具有惊人的旁观者效率。总的来说,这项研究表明,CP-506在肿瘤组织中具有良好的药理学特性,并支持其正在开发用于治疗晚期实体恶性肿瘤患者的方法.