Glenn G M, Szende B, Yano T, Zbar B, Borsos T
Laboratory of Immunobiology, NCI-FCRF, Frederick, MD 21701.
Int J Cancer. 1988 Jul 15;42(1):76-83. doi: 10.1002/ijc.2910420115.
Serotherapy and plasma therapy have proved to be effective in the treatment of diverse neoplasms. The mechanisms of the tumoricidal or growth-inhibitory effects are unknown. We previously reported that activation of the alternative pathway of complement in absorbed sera correlated with the presence of anti-tumor activity. Complement components generated during absorption may serve as the initial mediators of cytotoxicity; for example, C5a may function in its role as a chemo-attractant. To further investigate the anti-tumor mechanisms, we undertook a series of sequential histological studies of in vivo changes in tumors following i.v. serotherapy. We found diffuse inflammatory cellular infiltrates in the interstitial compartments of primary mammary carcinomas of rats within 3-4 hr of administration of protein A-Sepharose absorbed syngeneic serum. The number of inflammatory cells was significantly higher in tumors from treated rats: total infiltrating cells (p = 0.002), eosinophils (p = 0.001), neutrophils (p = 0.001), macrophages (p = 0.001), lymphocytes (p = 0.004) and plasma cells (p = 0.001). Also, the mitotic index of tumor cells was significantly lower 4 hr after serotherapy when compared with that of untreated rat tumor cells. C3 in tumor tissue was decreased at 4 hr following serotherapy. Fibrosis was present in tumor nodules with retarded growth 5 weeks after the start of serotherapy. Localization of the infiltrating cells to tumor interstitial compartments prevents direct contact between inflammatory cells and neoplastic cells, making it unlikely that direct cell-cell killing occurs. Indirect cell killing within the tumor bed apparently occurs through several mechanisms involving interactions between serotherapy-initiated humoral mediators and inflammatory cells. The resulting anti-tumor effects include microvascular injury leading to localized ischemia, tumor infarction, and fibroblastic reactions obstructing tumor invasion and growth.
血清疗法和血浆疗法已被证明在多种肿瘤的治疗中有效。其杀肿瘤或生长抑制作用的机制尚不清楚。我们之前报道过，吸收血清中补体替代途径的激活与抗肿瘤活性的存在相关。吸收过程中产生的补体成分可能作为细胞毒性的初始介质；例如，C5a可能发挥其作为趋化因子的作用。为了进一步研究抗肿瘤机制，我们对静脉注射血清疗法后肿瘤的体内变化进行了一系列连续的组织学研究。我们发现，在给予蛋白A - 琼脂糖吸收的同基因血清后3 - 4小时内，大鼠原发性乳腺癌的间质区出现弥漫性炎性细胞浸润。治疗组大鼠肿瘤中的炎性细胞数量显著更高：总浸润细胞（p = 0.002）、嗜酸性粒细胞（p = 0.001）、中性粒细胞（p = 0.001）、巨噬细胞（p = 0.001）、淋巴细胞（p = 0.004）和浆细胞（p = 0.001）。此外，与未治疗的大鼠肿瘤细胞相比，血清疗法后4小时肿瘤细胞的有丝分裂指数显著降低。血清疗法后4小时肿瘤组织中的C3减少。血清疗法开始5周后，生长迟缓的肿瘤结节中出现纤维化。浸润细胞定位于肿瘤间质区，阻止了炎性细胞与肿瘤细胞的直接接触，使得不太可能发生直接的细胞间杀伤。肿瘤床内的间接细胞杀伤显然是通过几种机制发生的，这些机制涉及血清疗法引发的体液介质与炎性细胞之间的相互作用。由此产生的抗肿瘤作用包括导致局部缺血的微血管损伤、肿瘤梗死和成纤维细胞反应，从而阻碍肿瘤的侵袭和生长。
