Carbon monoxide, generated by heme oxygenase-1, mediates the enhanced permeability and retention effect in solid tumors
Carbon monoxide, generated by heme oxygenase-1, mediates the enhanced permeability and retention effect in solid tumors
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DOI：
10.1111/j.1349-7006.2011.02178.x
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发表时间：
2012-03-01
期刊：
影响因子：
5.7
通讯作者：
Maeda, Hiroshi
中科院分区：
文献类型：
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作者：
Fang, Jun;Qin, Haibo;Maeda, Hiroshi
增强渗透性和滞留（EPR）效应是实体瘤独特的病理生理现象，生物相容性大分子（>40 kDa）选择性地在肿瘤中积累。这种影响涉及多种因素。在此，我们报道血红素加氧酶-1（HO-1；也称为热休克蛋白32）显着增加血管通透性，从而增加肿瘤中大分子药物的积累。小鼠皮内注射重组 HO-1，然后静脉注射。给予大分子伊文思蓝白蛋白复合物，导致 HO-1 注射部位伊文思蓝白蛋白剂量依赖性外渗。当注射灭活的 HO-1 或一氧化碳 (CO) 清除剂时，几乎没有检测到外渗。由于 HO-1 产生 CO，这些数据表明 CO 在血管渗漏中发挥着关键作用。在相同的实验环境中，肿瘤内施用 CO 释放剂（三羰基二氯钌（II）二聚体）后获得的结果支持了这一点，特别是血管通透性的剂量依赖性增加以及肿瘤血流量的增加。此外，水溶性大分子HO-1诱导剂聚乙二醇化血红素在肿瘤中诱导HO-1显着增加肿瘤血流量和伊文思蓝白蛋白在肿瘤中的积累。这些发现表明 HO-1 和/或 CO 是 EPR 效应的重要介质。因此，使用大分子药物的抗癌化疗可以通过与HO-1诱导剂（例如聚乙二醇化氯化血红素）组合来改善EPR效应。 （癌症科学 2012 年；103：535541）
The enhanced permeability and retention (EPR) effect is a unique pathophysiological phenomenon of solid tumors that sees biocompatible macromolecules (>40 kDa) accumulate selectively in the tumor. Various factors have been implicated in this effect. Herein, we report that heme oxygenase-1 (HO-1; also known as heat shock protein 32) significantly increases vascular permeability and thus macromolecular drug accumulation in tumors. Intradermal injection of recombinant HO-1 in mice, followed by i.v. administration of a macromolecular Evans bluealbumin complex, resulted in dose-dependent extravasation of Evans bluealbumin at the HO-1 injection site. Almost no extravasation was detected when inactivated HO-1 or a carbon monoxide (CO) scavenger was injected instead. Because HO-1 generates CO, these data imply that CO plays a key role in vascular leakage. This is supported by results obtained after intratumoral administration of a CO-releasing agent (tricarbonyldichlororuthenium(II) dimer) in the same experimental setting, specifically dose-dependent increases in vascular permeability plus augmented tumor blood flow. In addition, induction of HO-1 in tumors by the water-soluble macromolecular HO-1 inducer pegylated hemin significantly increased tumor blood flow and Evans bluealbumin accumulation in tumors. These findings suggest that HO-1 and/or CO are important mediators of the EPR effect. Thus, anticancer chemotherapy using macromolecular drugs may be improved by combination with an HO-1 inducer, such as pegylated hemin, via an enhanced EPR effect. (Cancer Sci 2012; 103: 535541)