Jain R K
Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213-3890.
Int J Radiat Biol. 1991 Jul-Aug;60(1-2):85-100. doi: 10.1080/09553009114551621.
The efficacy in cancer treatment of novel therapeutic agents such as monoclonal antibodies, cytokines and effector cells has been limited by their inability to reach their target in vivo in adequate quantities. Molecular and cellular biology of neoplastic cells alone has failed to explain the nonuniform uptake of these agents. This is not surprising since a solid tumour in vivo is not just a collection of cancer cells. In fact, it consists of two extracellular compartments: vascular and interstitial. Since no blood-borne molecule or cell can reach cancer cells without passing through these compartments, the vascular and interstitial physiology of tumours has received considerable attention in recent years. Three physiological factors responsible for the poor localization of macromolecules in tumours have been identified: (i) heterogeneous blood supply, (ii) elevated interstitial pressure, and (iii) large transport distances in the interstitium. The first factor limits the delivery of blood-borne agents to well-perfused regions of a tumour; the second factor reduces extravasation of fluid and macromolecules in the high interstitial pressure regions and also leads to an experimentally verifiable, radially outward convection in the tumour periphery which opposes the inward diffusion; and the third factor increases the time required for slowly moving macromolecules to reach distal regions of a tumour. Binding of the molecule to an antigen further lowers the effective diffusion rate by reducing the amount of mobile molecule. Although the effector cells are capable of active migration, peculiarities of the tumour vasculature and interstitium may also be responsible for poor delivery of lymphokine activated killer cells and tumour infiltrating lymphocytes in solid tumours. Due to micro- and macroscopic heterogeneities in tumours, the relative magnitude of each of these physiological barriers would vary from one location to another and from one day to the next in the same tumour, and from one tumour to another. If the genetically engineered macromolecules and effector cells, as well as low molecular weight cytotoxic agents, are to fulfill their clinical promise, strategies must be developed to overcome or exploit these barriers. Some of these strategies are discussed, and situations wherein these barriers may not be a problem are outlined. Finally, some therapies where the tumour vasculature of the interstitium may be a target are pointed out.
单克隆抗体、细胞因子和效应细胞等新型治疗药物在癌症治疗中的疗效一直受到限制，因为它们无法在体内足量到达靶点。仅肿瘤细胞的分子和细胞生物学无法解释这些药物摄取的不均匀性。这并不奇怪，因为体内实体瘤不仅仅是癌细胞的集合。事实上，它由两个细胞外间隙组成：血管间隙和间质间隙。由于任何血源性分子或细胞在到达癌细胞之前都必须穿过这些间隙，因此肿瘤的血管和间质生理学近年来受到了相当大的关注。已确定导致大分子在肿瘤中定位不佳的三个生理因素：（i）血液供应不均，（ii）间质压力升高，以及（iii）间质中传输距离大。第一个因素限制了血源性药物向肿瘤灌注良好区域的递送；第二个因素减少了高间质压力区域中液体和大分子的外渗，并且还导致肿瘤周边出现经实验验证的径向向外对流，这与向内扩散相反；第三个因素增加了缓慢移动的大分子到达肿瘤远端区域所需的时间。分子与抗原的结合通过减少可移动分子的数量进一步降低了有效扩散速率。尽管效应细胞能够主动迁移，但肿瘤脉管系统和间质的特殊性也可能是实体瘤中淋巴因子激活的杀伤细胞和肿瘤浸润淋巴细胞递送不佳的原因。由于肿瘤在微观和宏观上的异质性，这些生理屏障中每一个的相对大小在同一肿瘤的不同位置之间、不同时间之间以及不同肿瘤之间都会有所不同。如果基因工程大分子和效应细胞以及低分子量细胞毒性药物要实现其临床前景，就必须制定策略来克服或利用这些屏障。本文讨论了其中一些策略，并概述了这些屏障可能不成问题的情况。最后，指出了一些以肿瘤间质脉管系统为靶点的治疗方法。
