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

化疗药物 5-FU 和 CDDP 对口腔癌患者的细胞因子诱导和抗癌作用

• 批准号: 12671942
• 负责人: OKAMOTO Masato
• 金额: $ 2.24万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671942/
• 关键词: 5-FU; CDDP; Th1 cytokine; Killer cell activity; NK cells; anti-cancer immunity; 抗腫瘍活性

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

已有研究表明，某些化疗药物具有增强恶性肿瘤患者抗癌宿主反应的作用。在本研究中，我们研究了顺铂(CDDP)和5-氟尿嘧啶(5-FU)在体内和体外是否能诱导具有抗肿瘤活性的细胞因子和杀伤细胞。人外周血单个核细胞在含5-FU(0~5.0μg/ml)或顺铂的条件下培养。(0~1.0μg/ml)能显著增强NK细胞活性，并在体外产生干扰素-γ、肿瘤坏死因子-α、肿瘤坏死因子-β、白介素12和白介素18。所有这些活性几乎都是完全中和的，通过加入抗asialo-GML抗体和补体来消除NK细胞。此外，我们还研究了VitR…中细胞因子和杀伤细胞的诱导活性。PBMC上的这些药物更多地来自口腔癌患者。5-FU和CDDP在未经治疗的口腔癌患者以及治疗后的无病患者的PBMC中均可诱导Th1细胞因子和杀伤细胞。这些活性也被抗asialo-GML抗体和补体所中和。在体内模型中，抗asialo-GML抗体显著缩短了CDDP或5-FU对人涎腺肿瘤裸鼠和同基因Meth-A荷瘤BALB/c小鼠的存活时间。此外，在给予CDDP或5-FU的动物体内，检测到血清中高水平的Th1细胞因子和脾中NK细胞的活性。接下来，我们检测了接受顺铂治疗的口腔癌患者血清中Th1细胞因子和PBMC中杀伤细胞的活性。CDDP治疗后，患者外周血中Th1细胞因子水平和杀伤细胞活性均显著增加。1提示抗癌化疗药物5-FU和CDDP可通过诱导Th1细胞因子和杀伤细胞活性来增强口腔癌患者的抗癌免疫，NK细胞可能参与了5-FU和CDDP诱导的抗癌免疫。

项目成果

Masato Okamoto: "Induction of Th1-type cytokines by lipoteichoic acid-related preparation isolated from OK-432, a penicillin-killed streptococcal agent"Immunopharmacol. 49. 363-376 (2000)

Masato Okamoto：“通过从青霉素杀死链球菌剂 OK-432 中分离出的脂磷壁酸相关制剂诱导 Th1 型细胞因子”Immunopharmacol。

Okamoto M.: "Induction of Th1-type cytokines by lipoteichoic acid-related preparation isolated from OK-432, a penicillin-killed streptococcal agent"immunopharmacol. 49 (3). 363-376 (2000)

Okamoto M.：“通过从 OK-432（一种青霉素杀死链球菌剂）分离的脂磷壁酸相关制剂诱导 Th1 型细胞因子”immunopharmacol。

Masato Okamoto: "Role of Toll-loke receptor 4 gene in the effect of anti-cancer agents"Head and Neck Cancer. 27 (3). 651-657 (2001)

Masato Okamoto：“Toll-loke 受体 4 基因在抗癌药物作用中的作用”头颈癌。

大江 剛: "寄生植物ナンバンキセルよりサイトカイン誘導構造の分離"Biotherapy. 14. 514-517 (2000)

Tsuyoshi Oe：“从寄生植物 Nanb​​anxel 中分离细胞因子诱导结构”生物疗法 14. 514-517 (2000)。

Masato Okamoto: "Purification and characterization of cytokine-inducing protein of seed extract from Aeginetia indica L, a parasitic plant"Immunopharmacol. 49. 377-389 (2000)

Masato Okamoto：“寄生植物 Aeginetia indica L 种子提取物的细胞因子诱导蛋白的纯化和表征”Immunopharmacol。