Cytokine-inducing and anti-cancer effects of 5-FU and CDDP, chemotherapeutic agents, in oral cancer patients

据报道，某些化疗药物在恶性疾病患者中表现出增强抗癌宿主反应的作用。本研究探讨了顺铂（CDDP）和5-氟尿嘧啶（5-FU）能否在体内外诱导产生具有抗癌作用的细胞因子和杀伤细胞。在存在5-FU（0至5.0 μg/ml）或CDDP的情况下培养来自健康供体的人外周血单核细胞（PBMC）。0 ~ 1.0 μg/ml浓度范围内，在体外可显著增强NK细胞活性，并产生干扰素（IFN）-γ、肿瘤坏死因子（TNF）-α、TNF-β、白细胞介素（IL）-12和IL-18等Th 1型细胞因子。所有这些活性通过添加抗脱唾液酸基-GMl抗体和补体消除NK细胞而几乎完全中和。此外，我们还研究了体外细胞因子和杀伤细胞诱导活性， ...更多信息 o这些药物对来源于口腔癌患者的PBMC的作用。5-FU和CDDP都能在未经治疗的口腔癌患者以及经治疗的无病患者的PBMC中诱导Th 1细胞因子和杀伤细胞。这些活性也被抗脱唾液酸基-GM 1抗体和补体中和。在体内模型中，抗去唾液酸-GM 1抗体的施用显著缩短了在携带人唾液腺肿瘤的裸鼠和携带同基因Meth-A肿瘤的BALB/c小鼠中通过用CDDP或5-FU治疗而延长的存活时间。此外，检测到来自给予CDDP或5-FU的动物的血清中高水平的Thl细胞因子和脾细胞中高水平的NK细胞活性。接下来，我们检测了用CDDP治疗的口腔癌患者血清中的Th 1细胞因子和PBMC的杀伤细胞活性。CDDP治疗后，患者血清中Th 1细胞因子含量和PBMC中Th 1细胞活性均显著增加。1这些结果提示，5-FU和CDDP作为抗癌化疗药物，通过诱导Th 1细胞因子和杀伤细胞活性，增强口腔癌患者的抗癌免疫，NK细胞可能密切参与了5-FU和CDDP诱导的抗癌免疫。基于本研究的结果，我们将建立一个能提高口腔癌患者抗肿瘤反应的化疗方案。少

It has been reported that certain chemotherapeutic agents exhibit the effects to enhance the anti cancer host responses in the patients with malignant diseases. In the present study, we investigated whether Cis-diamminedichloroplatinum (CDDP) and 5-Fluorouracil (5-FU) may induce cytokines and killer cells carrying anti-cancer efficiency in vivo and in vitro. The cultivation of human peripheral blood mononuclear cells (PBMC) derived from healthy donors in the presence of 5-FU (0 to 5.0 μg/ml) or CDDP. (0 to 1.0 μg/ml) resulted in the significant augmentation of natural killer (NK) cell activities as well as generation of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, TNF-β, interleukin (IL)-12 and IL-18 that are generally called "Th1-type cytokines"in vitro. All of these activities were almost i completely neutralized by eliminating NK cells by addition of anti-asialo-GMl antibody and complement. In addition, we also investigated cytokine- and killer cell-inducing activities in vitr … More o of these agents on the PBMC derived from oral cancer patients. Both 5-FU and CDDP induced Thl cytokines and killer cells in the PBMC from untreated oral cancer patients as well as from treated, disease-free pateients. These activities were also neutralized by anti-asialo-GMl antibody and complement. In in vivo model, the administration of anti-asialo-GMl antibody significantly shortened the survival time extended by the treatment with CDDP or 5-FU both in human salivary gland tumor-bearing nude mice and in syngeneic Meth-A tumor-bearing BALB/c mice. Furthermore, high levels of Thl cytokines in the sera and of NK-cell activity in the spleen.cells derived from animals given CDDP or 5-FU was detected. Next, we examined Thl cytokines in the sera and killer.cell activity of the PBMC in oral cancer patients treated with CDDP. Both Thl-cytokine 'amounts in the sera and killer-cell activities of the PBMC were significantly increased after CDDP administration.1 These findings suggest that 5-FU and CDDP, chemotherapeutic-agents against cancer, increase anti-cancer immunity mediated by induction of Thl cytokines and killer cell activities in the patients with oral cancer and that NK cells may be qlosely involved in 5-FU- and CDDP-induced anti-cancer immunity. Based on the results from the current study, we will establish the protocol for cancer chemotherapy that can increase anti-cancer host responses in oral cancer parients. Less