Brutkiewicz R R, Suzuki F
Department of Internal Medicine, University of Texas Medical Branch, Galveston 77550.
In Vivo. 1987 Jul-Aug;1(4):189-203.
The biological activities and antitumor mechanism of an immunopotentiator, Ge-132, is reviewed herein. Ge-132 exhibited antitumor activity against certain syngeneic and allogeneic experimental tumors. It was shown that T-cells and macrophages were involved when tumor-bearing mice were protected by the compound. This protective effect could be transferred to tumor-bearing mice, not treated with the compound, by a macrophage fraction and serum specimens obtained from Ge-132-treated mice. Interferon gamma (IFN gamma) was detected in the circulation of Ge-132-treated mice and when sera obtained from Ge-132-treated mice were treated with anti-IFN gamma antiserum in vitro, the antitumor activity was abolished. On the other hand, in mice treated with anti-IFN gamma antiserum, Ge-132 did not induce serum IFN and failed to protect against death due to ascites tumor progression. The in vivo administration of monoclonal anti-Thy 1.2 antibody prevented the expression of the antitumor activity of Ge-132. However, serum specimens obtained from Ge-132-treated mice effectively inhibited the tumor growth of T-cell-depleted mice bearing ascites tumors. Since it has been reported that T-lymphocytes produce IFN gamma, this suggested that Ge-132 may first stimulate T-cells to produce IFN gamma in the expression of the observed antitumor efficacy. In addition, sera obtained from Ge-132-treated mice did not show any antitumor activity in mice depleted of macrophage functions. Additionally, passive transfer of macrophages from mice treated with these serum specimens to tumor-bearing mice also resulted in the inhibition of tumor growth. Pretreatment of these serum specimens with anti-IFN gamma antiserum effectively prevented the generation of cytotoxic macrophages. Also, tumor-bearing mice treated exogenously with this antiserum did not differ significantly in survival as compared to controls, despite the administration of Ge-132. Furthermore, the antitumor activity of Ge-132 was detected in NK cell-depleted mice. Therefore, the antitumor mechanism of Ge-132 in the murine ascites tumor system may be expressed as follows: (a) Ge-132 stimulates T-cells to induce IFN gamma when mice are treated orally with the compound, (b) IFN gamma activates macrophages to become cytotoxic, and (c) the cytotoxic macrophages eliminate tumor cells.
本文综述了免疫增强剂Ge - 132的生物学活性及抗肿瘤机制。Ge - 132对某些同基因和异基因实验性肿瘤具有抗肿瘤活性。结果表明，当荷瘤小鼠受到该化合物保护时，T细胞和巨噬细胞参与其中。这种保护作用可以通过从Ge - 132处理的小鼠中获得的巨噬细胞组分和血清标本传递给未用该化合物处理的荷瘤小鼠。在Ge - 132处理的小鼠循环中检测到γ干扰素（IFNγ），并且当在体外将从Ge - 132处理的小鼠中获得的血清用抗IFNγ抗血清处理时，抗肿瘤活性被消除。另一方面，在用抗IFNγ抗血清处理的小鼠中，Ge - 132未诱导血清IFN，并且未能预防因腹水肿瘤进展导致的死亡。体内给予单克隆抗Thy 1.2抗体可阻止Ge - 132抗肿瘤活性的表达。然而，从Ge - 132处理的小鼠中获得的血清标本有效地抑制了荷腹水肿瘤的T细胞耗竭小鼠的肿瘤生长。由于已有报道T淋巴细胞产生IFNγ，这表明Ge - 132在观察到的抗肿瘤功效的表达中可能首先刺激T细胞产生IFNγ。此外，从Ge - 132处理的小鼠中获得的血清在巨噬细胞功能耗竭的小鼠中未显示任何抗肿瘤活性。另外，将用这些血清标本处理的小鼠的巨噬细胞被动转移到荷瘤小鼠中也导致肿瘤生长受到抑制。用抗IFNγ抗血清对这些血清标本进行预处理有效地阻止了细胞毒性巨噬细胞的产生。而且，尽管给予了Ge - 132，但用这种抗血清进行外源性处理的荷瘤小鼠与对照组相比在存活率上没有显著差异。此外，在NK细胞耗竭的小鼠中检测到Ge - 132的抗肿瘤活性。因此，Ge - 132在小鼠腹水肿瘤系统中的抗肿瘤机制可能如下：（a）当小鼠口服该化合物时，Ge - 132刺激T细胞诱导IFNγ，（b）IFNγ激活巨噬细胞使其具有细胞毒性，（c）细胞毒性巨噬细胞消除肿瘤细胞。
