Jain R K
Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213-3890.
Cancer Res. 1990 Feb 1;50(3 Suppl):814s-819s.
The efficacy in cancer treatment of monoclonal antibodies or other macromolecules bound to radionuclides, chemotherapeutic agents, toxins, enzymes, growth factors, or effector antibodies has been limited by their inability to reach their target in vivo in adequate quantities. Heterogeneity of tumor-associated antigen expression alone has failed to explain the nonuniform uptake of antibodies. As a result, only in recent years have the peculiarities of tumor physiology been recognized as determinants of antibody distribution. Three physiological barriers responsible for the poor localization of macromolecules in tumors have been identified: (a) heterogeneous blood supply; (b) elevated interstitial pressure; and (c) large transport distances in the interstitium. The first barrier limits the delivery of blood-borne molecules to well-perfused regions of a tumor; the second barrier reduces extravasation of fluid and macromolecules in the high interstitial pressure regions and also leads to an experimentally verifiable, radially outward convection in the tumor periphery which opposes the inward diffusion; and the third barrier increases the time required for slowly moving macromolecules to reach distal regions of a tumor. Binding of antibody to an antigen further lowers the effective diffusion rate of the antibody by reducing the amount of mobile antibody. Due to micro- and macroscopic heterogeneities in tumors, the relative magnitude of each of these barriers would vary from one location to another and from one day to the next in the same tumor and from one tumor to another. If the genetically engineered macromolecules, e.g., lymphokines, and other new modalities, e.g., killer lymphocytes, as well as low molecular weight cytotoxic agents, are to fulfill their clinical promise, methods must be developed to overcome these physiological barriers. Some of these methods are discussed, and situations wherein these barriers may not be a problem are pointed out.
与放射性核素、化疗药物、毒素、酶、生长因子或效应抗体结合的单克隆抗体或其他大分子在癌症治疗中的疗效，一直受到其在体内无法足量到达靶点的限制。仅肿瘤相关抗原表达的异质性并不能解释抗体摄取的不均匀性。因此，直到近年来，肿瘤生理学的特殊性才被确认为抗体分布的决定因素。已确定三种导致大分子在肿瘤中定位不佳的生理屏障：(a) 血液供应不均；(b) 间质压力升高；(c) 间质中的运输距离较长。第一道屏障限制了血源分子向肿瘤灌注良好区域的输送；第二道屏障减少了高间质压力区域中液体和大分子的外渗，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；第三道屏障增加了缓慢移动的大分子到达肿瘤远端区域所需的时间。抗体与抗原的结合通过减少可移动抗体的量进一步降低了抗体的有效扩散速率。由于肿瘤中的微观和宏观异质性，这些屏障中每一种的相对大小在同一肿瘤的不同位置、不同时间以及不同肿瘤之间都会有所不同。如果基因工程大分子（如淋巴因子）和其他新方法（如杀伤淋巴细胞）以及低分子量细胞毒性药物要实现其临床前景，就必须开发克服这些生理屏障的方法。本文讨论了其中一些方法，并指出了这些屏障可能不成问题的情况。
