Maeda Hiroshi, Fang Jun, Inutsuka Takao, Kitamoto Yasunori
Department of Microbiology, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto 860-0811, Japan.
Int Immunopharmacol. 2003 Mar;3(3):319-28. doi: 10.1016/S1567-5769(02)00271-0.
Most solid tumors are known to exhibit highly enhanced vascular permeability, similar to or more than the inflammatory tissues. Common denominators affecting both cancer and inflammatory lesions are now well known: bradykinin (BK), nitric oxide (NO), peroxynitrite (ONOO(-)), prostaglandins (PGs), collagenases or matrix metalloproteinases (MMPs) and others. Incidentally, enzymes involved in these mediator syntheses are upregulated or activated. Initially described vascular permeability factor (VPF) (proteinaceous) was later identified to be the same as vascular endothelial growth factor (VEGF), which promotes angiogenesis of cancer tissues as well. These mediators cross-talk or co-upregulate each other, such as BK-NO-PGs system. Therefore, vascular permeability observed in solid tumor may reflect the other side of the coin (angiogenesis). The vascular permeability and accumulation of plasma components in the interstitium described here is applicable for predominantly macromolecules (molecular weight, Mw>45 kDa), but not for low molecular compounds as most anticancer agents are. Macromolecular compounds (e.g., albumin, transferrin) or many biocompatible water-soluble polymers show this effect. Furthermore, they are not cleared rapidly from the sites of lesion (cancer/inflammatory tissue), thus, remain for prolonged time, usually for more than a few days. This phenomenon of "enhanced permeability and retention effect" observed in cancer tissue for macromolecules and lipids is coined "EPR effect", which is now widely accepted as a gold standard for anticancer drug designing to seek more cancer-selective targeting using macromolecular drugs. Consequently, drastic reduction of the systemic side effect is observed, while the macromolecular drugs will continuously exert antitumor activity. Other advantages of macromolecular drugs are also discussed.
众所周知，大多数实体瘤表现出高度增强的血管通透性，类似于或超过炎症组织。影响癌症和炎症病变的共同因素现已为人熟知：缓激肽（BK）、一氧化氮（NO）、过氧亚硝酸盐（ONOO(-)）、前列腺素（PGs）、胶原酶或基质金属蛋白酶（MMPs）等。顺便提一下，参与这些介质合成的酶会被上调或激活。最初描述的血管通透性因子（VPF）（蛋白质类）后来被确定与血管内皮生长因子（VEGF）相同，VEGF也促进癌组织的血管生成。这些介质相互作用或共同上调，例如BK-NO-PGs系统。因此，实体瘤中观察到的血管通透性可能反映了问题的另一面（血管生成）。这里描述的间质中血管通透性和血浆成分的蓄积主要适用于大分子（分子量，Mw>45 kDa），但不适用于大多数抗癌药物那样的低分子化合物。大分子化合物（如白蛋白、转铁蛋白）或许多生物相容性水溶性聚合物具有这种作用。此外，它们不会从病变部位（癌症/炎症组织）迅速清除，因此会停留较长时间，通常超过几天。在癌症组织中观察到的大分子和脂质的“增强通透性和滞留效应”这一现象被称为“EPR效应”，现在它已被广泛接受为抗癌药物设计的金标准，即使用大分子药物寻求更具癌症选择性的靶向作用。因此，观察到全身副作用大幅降低，而大分子药物将持续发挥抗肿瘤活性。文中还讨论了大分子药物的其他优点。
