Sredni B, Tichler T, Shani A, Catane R, Kaufman B, Strassmann G, Albeck M, Kalechman Y
Marilyn Finkler Cancer Research Center, Department of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
J Natl Cancer Inst. 1996 Sep 18;88(18):1276-84. doi: 10.1093/jnci/88.18.1276.
Several studies have recently suggested that the immune response to malignant growths is regulated by distinct patterns of type 2 cytokine production. These cytokines, regulating the cytotoxic T-lymphocyte response in patients with advanced cancers, may be associated with disease progression. Evidence suggests that the T Helper 1 (TH1) and T Helper 2 (TH2) types of reaction are reciprocally regulated in vivo. The immunomodulator AS101 (ammonium trichloro[dioxoethylene-O,O']tellurate) was found to stimulate mouse and human cells to proliferate and secrete a variety of cytokines. Clinical trials using AS101 on cancer patients are now in progress.
The aim of this study was to evaluate the ability of AS101 to modulate TH1 and TH2 responses in tumor-bearing mice and in patients with advanced cancer. In addition, we investigated the association between the predominance of each type of response with the antitumoral effects of AS101.
Mice into which Lewis lung carcinoma (3LL) had been transplanted (n = 221) and cancer patients (n = 13) were treated with AS101 on alternate days, at 10 micrograms/mouse intraperitoneally, or for the patients, at 3 mg/m2 intravenously. The types were sarcoma, melanoma, and colon, lung, ovarian, and renal cancers. Cytokine levels were determined by immunoassay kits and compared with the paired Student's t test: in mice, they were tested in spleen cell supernatants; in humans, in sera and mononuclear cell supernatants. The chi-squared test was used to compare tumor volumes. All P values represent two-sided tests of statistical significance.
Our results show that treatment of mice and patients with AS101 results in a clear predominance in TH1 responses, with a concomitant decrease in the TH2-type response. This was reflected by a significant enhancement in interleukin 2 (IL-2) and interferon gamma (IFN gamma) levels (P < .01) paralleled by a substantial decrease in IL-4 and IL-10 (P < .01). Moreover, the concentration of IL-12 was significantly increased (P < .01) in AS101-treated patients who also showed enhanced levels of natural and lymphokine-activated killer cell-mediated cytotoxicity. The statistically significant increases in IL-2 and IFN gamma levels, paralleled by the pronounced decrease in IL-4 and IL-10 in the AS101-treated mice, were associated with its antitumoral effects. In addition, systemic cotreatment of 3LL-transplanted mice with AS101 and anti-IL-12 antibodies partly abrogated the antitumoral effect of AS101.
Immunotherapy with AS101 enhances TH1 function while interfering with the TH2 response. This TH1 trend may be related to the antitumor effects of AS101.
Isolation and characterization of a distinct cytokine pattern in patients with advanced cancer treated with AS101 may contribute to the development of intervention strategies using this compound.
最近的几项研究表明，对恶性肿瘤的免疫反应受2型细胞因子产生的不同模式调控。这些调节晚期癌症患者细胞毒性T淋巴细胞反应的细胞因子可能与疾病进展有关。有证据表明，体内1型辅助性T细胞（TH1）和2型辅助性T细胞（TH2）反应相互调节。免疫调节剂AS101（三氯[二氧乙烯-O,O']碲酸铵）可刺激小鼠和人类细胞增殖并分泌多种细胞因子。目前正在对癌症患者进行使用AS101的临床试验。
本研究旨在评估AS101调节荷瘤小鼠和晚期癌症患者TH1和TH2反应的能力。此外，我们研究了每种反应优势与AS101抗肿瘤作用之间的关联。
将接种Lewis肺癌（3LL）的小鼠（n = 221）和癌症患者（n = 13）每隔一天用AS101治疗，小鼠腹腔注射剂量为10微克/只，患者静脉注射剂量为3毫克/平方米。癌症类型包括肉瘤、黑色素瘤、结肠癌、肺癌、卵巢癌和肾癌。通过免疫分析试剂盒测定细胞因子水平，并与配对的学生t检验进行比较：在小鼠中，在脾细胞上清液中检测；在人类中，在血清和单核细胞上清液中检测。采用卡方检验比较肿瘤体积。所有P值均代表双侧统计学显著性检验。
我们的结果表明，用AS101治疗小鼠和患者会导致TH1反应明显占优势，同时TH2型反应相应降低。这表现为白细胞介素2（IL-2）和干扰素γ（IFNγ）水平显著升高（P <.01），同时IL-4和IL-10大幅下降（P <.01）。此外，在接受AS101治疗的患者中，IL-12浓度显著升高（P <.01），这些患者的自然杀伤细胞和淋巴因子激活的杀伤细胞介导的细胞毒性水平也有所提高。在接受AS101治疗的小鼠中，IL-2和IFNγ水平的统计学显著升高，同时IL-4和IL-10明显降低，这与其抗肿瘤作用相关。此外，用AS101和抗IL-12抗体对移植3LL的小鼠进行全身联合治疗，部分消除了AS101的抗肿瘤作用。
用AS101进行免疫治疗可增强TH1功能，同时干扰TH2反应。这种TH1趋势可能与AS101的抗肿瘤作用有关。
对接受AS101治疗的晚期癌症患者独特细胞因子模式的分离和表征，可能有助于开发使用该化合物的干预策略。
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