Gan X H, Jewett A, Bonavida B
Department of Microbiology and Immunology, UCLA School of Medicine.
Nat Immun. 1992 May-Jun;11(3):144-55.
The anticancer agent cis-diamminedichloroplatinum (CDDP) has been shown to have immunopotentiating and immuno-suppressive properties depending on the CDDP concentration used. Treatment of human peripheral-blood-derived monocytes (PBM) in vitro with low concentrations of CDDP resulted in a significant potentiation of antitumor cytotoxicity as assessed in an 18-hour 51Cr release assay. The potentiation of cytotoxicity by CDDP was also observed with PBM treated with recombinant interferon-gamma (rIFN-gamma). The monocyte-mediated cytotoxicity was significantly inhibited when antitumor necrosis factor (TNF) antibody was added to the assay culture. The role of TNF in the cytotoxic mechanism was further corroborated by demonstrating that significant levels of immunoreactive TNF-alpha in the supernatants were detected by ELISA. Further, supernatants derived from CDDP-treated monocytes were cytotoxic to the TNF-sensitive tumor cells and the cytotoxicity was neutralized by the addition of anti-TNF antibody. The secretion of TNF-alpha by CDDP-treated monocytes was readily detected as early as 4 h after culture and was dependent on de novo protein synthesis as inhibitors of RNA and protein synthesis abolished TNF-alpha secretion. Altogether, these results demonstrate that CDDP can potentiate monocyte-mediated antitumor cytotoxicity and stimulates TNF-alpha synthesis and secretion.
抗癌药物顺二氯二氨铂（CDDP）已被证明根据所用CDDP浓度具有免疫增强和免疫抑制特性。在体外使用低浓度的CDDP处理人外周血来源的单核细胞（PBM），在18小时的51Cr释放试验中评估，导致抗肿瘤细胞毒性显著增强。在用重组干扰素-γ（rIFN-γ）处理的PBM中也观察到CDDP对细胞毒性的增强作用。当在试验培养物中加入抗肿瘤坏死因子（TNF）抗体时，单核细胞介导的细胞毒性被显著抑制。通过ELISA证明上清液中检测到显著水平的免疫反应性TNF-α，进一步证实了TNF在细胞毒性机制中的作用。此外，来自CDDP处理的单核细胞的上清液对TNF敏感的肿瘤细胞具有细胞毒性，并且通过加入抗TNF抗体可中和细胞毒性。早在培养后4小时就很容易检测到CDDP处理的单核细胞分泌TNF-α，并且其依赖于从头蛋白质合成，因为RNA和蛋白质合成抑制剂消除了TNF-α的分泌。总之，这些结果表明CDDP可以增强单核细胞介导的抗肿瘤细胞毒性，并刺激TNF-α的合成和分泌。
