Pharmacokinetics and biodistribution of recombinant human plasminogen activator inhibitor type 2 (PAI 2) in control and tumour xenograft-bearing mice
Pharmacokinetics and biodistribution of recombinant human plasminogen activator inhibitor type 2 (PAI 2) in control and tumour xenograft-bearing mice
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DOI：
10.1016/s0268-9499(98)80296-8
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发表时间：
1998-05-01
期刊：
影响因子：
--
通讯作者：
Baker, MS
中科院分区：
文献类型：
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作者：
Hang, MTN;Ranson, M;Baker, MS
目的：既往研究表明，肿瘤细胞中人纤溶酶原激活剂抑制剂2型（PAI-2）的内源性过度表达会降低其生长和转移能力。然而，PAI-2 的治疗效用仍然缺乏评估。在本研究中，在人类结肠癌异种移植 Nu/Nu 小鼠模型中测定了重组人 PAI-2 的动力学和生物分布，并与对照小鼠（即没有人类异种移植肿瘤）进行了比较。设计：静脉注射 I-125 标记的重组 PAI-2，并在对照 Nu/Nu 小鼠或皮下携带 HCT116 人类结肠癌异种移植物的小鼠中测定药代动力学和生物分布。研究发现 I-125-PAI-2 从小鼠血浆中的清除是一个双相过程，放射性物质以降解形式通过尿液排出体外。虽然与完整 PAI-2 相对应的放射性很快定位于肿瘤异种移植组织（1 分钟后，注射剂量的 1.3% 后 30-60 分钟后达到峰值），但在荷瘤小鼠和对照小鼠中静脉注射 I-125-PAI-2 后 5 分钟，大部分放射性定位于主要器官（例如肝脏、肾脏）。然而，与肿瘤组织相比，这些器官中的放射性清除速度更快。此外，多次注射 I-125-PAI-2 导致肿瘤异种移植物中放射性的吸收增加，而肝脏中的放射性吸收却没有增加。此外，肿瘤异种移植物的存在显着增加了清除率，这表明需要在患病动物和对照动物中进行药代动力学研究。结论：我们的结果提供了有关 PAI-2 药代动力学和生物分布的重要信息，并表明肿瘤的存在可能会影响这些参数。此外，PAI-2 在肿瘤组织中的定位和积累表明其在人类癌症中具有潜在的治疗用途。
Objective: Previous studies have shown that the endogenous overexpression of human plasminogen activator inhibitor type-2 (PAI-2) in tumour cells decrease their ability to grow and metastasise. The therapeutic utility of PAI-2, however, remains poorly evaluated. In this study the kinetics and biodistribution of recombinant human PAI-2 were determined in a xenograft Nu/Nu mouse model of human colon cancer and compared to control mice (i.e. without a human xenograft tumour).Design: I-125-labelled recombinant PAI-2 was injected intravenously and the pharmacokinetics and biodistribution determined in control Nu/Nu mice or mice carrying a subcutaneous HCT116 human colon cancer xenograft.Results: The clearance of I-125-PAI-2 from mouse plasma was found to be a biphasic process and radioactivity was excreted via the urine in a degraded form. While radioactivity corresponding to intact PAI-2 localized to tumour xenograft tissues quickly (after 1 min, peaking after 30-60 min at 1.3% of injected dose), the majority of radioactivity localized to major organs (e.g, liver, kidneys) 5 min after intravenous injection of I-125-PAI-2 in both tumour bearing and control mice. However, radioactivity was cleared more rapidly from these organs when compared to tumour tissues. Moreover, multiple injections of I-125-PAI-2 resulted in an increased uptake of radioactivity in tumour xenografts without accompanying increases in the liver. Furthermore, the clearance rate was markedly increased by the presence of a tumour xenograft indicating the requirement to undertake pharmacokinetic studies in diseased as well as control animals.Conclusion: Our results provide important information concerning the pharmacokinetics and biodistribution of PAI-2 and indicates that the presence of a tumour may affect these parameters. Moreover, the localization and accumulation of PAI-2 in tumour tissues argues for a potential therapeutic use in human cancer.