ten Hagen Timo L M, Seynhaeve Ann L B, Eggermont Alexander M M
Department of Surgical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Immunol Rev. 2008 Apr;222:299-315. doi: 10.1111/j.1600-065X.2008.00619.x.
Solid tumor therapy with chemotherapeutics greatly depends on the efficiency with which drugs are delivered to tumor cells. The typical characteristics of the tumor physiology promote but also appose accumulation of blood-borne agents. The leaky tumor vasculature allows easy passage of drugs. However, the disorganized vasculature causes heterogeneous blood flow, and together with the often-elevated interstitial fluid pressure, this state results in poor intratumoral drug levels and failure of treatment. Manipulation of the tumor vasculature could overcome these barriers and promote drug delivery. Targeting the vasculature has several advantages. The endothelial lining is readily accessible and the first to be encountered after systemic injection. Second, endothelial cells tend to be more stable than tumor cells and thus less likely to develop resistance to therapy. Third, targeting the tumor vasculature can have dual effects: (i) manipulation of the vasculature can enhance concomitant chemotherapy, and (ii) subsequent destruction of the vasculature can help to kill the tumor. In particular, tumor necrosis factor alpha is studied. Its action on solid tumors, both directly through tumor cell killing and destruction of the tumor vasculature and indirectly through manipulation of the tumor physiology, is complex. Understanding the mechanism of TNF and agents with comparable action on solid tumors is an important focus to further develop combination immunotherapy strategies.
使用化疗药物进行实体瘤治疗在很大程度上取决于药物输送到肿瘤细胞的效率。肿瘤生理学的典型特征既促进又阻碍血源药物的蓄积。肿瘤血管渗漏使药物易于通过。然而，杂乱无章的血管导致血流不均，再加上通常升高的间质液压力，这种状态导致肿瘤内药物水平低下和治疗失败。对肿瘤血管系统进行调控可以克服这些障碍并促进药物递送。靶向血管系统有几个优点。内皮细胞层易于接近，并且在全身注射后首先接触到。其次，内皮细胞往往比肿瘤细胞更稳定，因此对治疗产生耐药性的可能性更小。第三，靶向肿瘤血管系统可产生双重作用：（i）对血管系统的调控可增强同步化疗，（ii）随后对血管系统的破坏有助于杀死肿瘤。特别是，对肿瘤坏死因子α进行了研究。它对实体瘤的作用很复杂，既可以直接通过杀死肿瘤细胞和破坏肿瘤血管系统，也可以间接通过调控肿瘤生理学来实现。了解肿瘤坏死因子以及对实体瘤有类似作用的药物的作用机制是进一步开发联合免疫治疗策略的一个重要重点。
