Wang B S, Lumanglas A L, Ruszala-Mallon V M, Durr F E
J Immunol. 1985 Jul;135(1):679-83.
3,6-bis(2-piperidinoethoxy)acridine trihydrochloride (CL 246,738) has been investigated for its immunomodulatory effect on murine macrophages. Incubation of macrophages harvested from the peritoneal cavities of normal mice with the compound for 48 to 72 hr rendered these cells inhibitory to the growth of tumor cells in vitro. Activation of tumor-inhibitory macrophages occurred over a range of concentrations (0.025 to 0.1 micrograms/ml) producing no direct inhibitory effects on tumor cells. Treatment of effector cells with carrageenan abrogated the effect, whereas treatment with anti-Thy-1.2 antibody and C did not, suggesting that the primary effectors were macrophages rather than T lymphocytes. These activated macrophages also manifested in vitro tumor cytolysis. In vivo studies indicated that peritoneal macrophages from mice treated with single oral doses of 100 to 400 mg/kg of the compound were also inhibitory to tumor cell growth in vitro. Effector macrophages became demonstrable in mice as early as 1 day after drug administration, reached peak activity at day 12, and disappeared by day 31, indicating a rapid onset but long-persisting effect. The tumor cytostatic activity of these macrophages was augmented by endotoxin at the dose of endotoxin that, in itself, had no effect. The addition of protease inhibitors, N-alpha-p-tosyl-L-lysine chloromethyl ketone and aprotinin, to cultures markedly diminished the cytostatic effect, suggesting that the release of neutral protease(s) could account for the inhibitory effects of the macrophages. On the other hand, hydrogen peroxide and arginase seemed excluded as the mechanism of action because the effect was not sensitive to treatment with catalase and exogenous arginine. The present findings indicate that CL 246,738 is an orally active immunopotentiator capable of inducing tumor-inhibitory macrophages both in vitro and in vivo.
3,6 - 双（2 - 哌啶基乙氧基）吖啶三盐酸盐（CL 246,738）已被研究其对小鼠巨噬细胞的免疫调节作用。将从正常小鼠腹腔收获的巨噬细胞与该化合物孵育48至72小时，使这些细胞在体外对肿瘤细胞的生长具有抑制作用。肿瘤抑制性巨噬细胞的激活发生在一系列浓度范围内（0.025至0.1微克/毫升），对肿瘤细胞没有直接抑制作用。用角叉菜胶处理效应细胞可消除该作用，而用抗Thy - 1.2抗体和补体C处理则不能，这表明主要效应细胞是巨噬细胞而非T淋巴细胞。这些活化的巨噬细胞在体外也表现出肿瘤细胞溶解作用。体内研究表明，单次口服剂量为100至400毫克/千克该化合物处理的小鼠的腹腔巨噬细胞在体外也对肿瘤细胞生长具有抑制作用。效应巨噬细胞在给药后1天在小鼠体内即可检测到，在第12天达到峰值活性，并在第31天消失，表明起效迅速但作用持久。这些巨噬细胞的肿瘤细胞生长抑制活性在内毒素剂量本身无作用的情况下，可被内毒素增强。向培养物中添加蛋白酶抑制剂N - α - 对甲苯磺酰 - L - 赖氨酸氯甲基酮和抑肽酶可显著降低细胞生长抑制作用，这表明中性蛋白酶的释放可能是巨噬细胞产生抑制作用的原因。另一方面，过氧化氢和精氨酸酶似乎被排除在作用机制之外，因为该作用对过氧化氢酶和外源性精氨酸处理不敏感。目前的研究结果表明，CL 246,738是一种口服活性免疫增强剂，能够在体外和体内诱导肿瘤抑制性巨噬细胞。
