Yamada M, Ohkawa M, Tamura K, Mabuchi E, Kishima H, Tamura M, Shimizu K
Department of Neurosurgery, Osaka University Medical School, Suita City, Japan.
J Neurooncol. 2000 Apr;47(2):125-32. doi: 10.1023/a:1006410311412.
It is well known that phenytoin can cause impairment of cellular immunity. The authors investigated the potential role of other anticonvulsant drugs in the development of antitumor immunity in murine malignant glioma models. The survival rate was determined in murine glioma models using syngeneic 203 glioma cells following treatment with four anticonvulsants, which are most commonly administered to glioma patients, i.e., phenytoin, phenobarbital, valproate and zonisamide. In a second set of experiments, we further examined the effect of these drugs on interferon-gamma (IFN-gamma) secretion by lymphocytes prepared from cervical lymph nodes (CLN) in the same models. The IFN-gamma production of CLN lymphocytes as measured by ELISA method was markedly impaired in the early stage of tumor-bearing mice treated with phenytoin or zonisamide, and the median survival time (MST) of controls and of mice treated with either phenytoin or zonisamide was 13, 10 and 11 days, respectively, which was not a statistically significant difference. Phenobarbital and valproate did not affect either IFN-gamma production or their survival rate. In addition, immunohistochemistry showed a reduction in tumor-infiltrating lymphocytes containing CD4 and CD8 antigens in the mice treated with phenytoin and zonisamide. Two anticonvulsants, phenytoin and zonisamide, showed a significant inhibitory effect on IFN-gamma production by CLN lymphocytes in murine glioma models, although there was no statistically significant difference in MST between controls and the anticonvulsant-treated mice. These drugs might have some detrimental influence on the prognosis of brain tumor patients when combined with the latent immune dysfunction accompanying the tumor-bearing state.
众所周知，苯妥英可导致细胞免疫功能受损。作者在小鼠恶性胶质瘤模型中研究了其他抗惊厥药物在抗肿瘤免疫发展中的潜在作用。在用四种最常用于胶质瘤患者的抗惊厥药物（即苯妥英、苯巴比妥、丙戊酸盐和唑尼沙胺）治疗后，使用同基因203胶质瘤细胞在小鼠胶质瘤模型中测定存活率。在第二组实验中，我们进一步研究了这些药物对同一模型中从颈淋巴结（CLN）制备的淋巴细胞分泌干扰素-γ（IFN-γ）的影响。用ELISA法测定，在用苯妥英或唑尼沙胺治疗的荷瘤小鼠早期，CLN淋巴细胞的IFN-γ产生明显受损，对照组以及用苯妥英或唑尼沙胺治疗的小鼠的中位生存时间（MST）分别为13天、10天和11天，差异无统计学意义。苯巴比妥和丙戊酸盐对IFN-γ产生或存活率均无影响。此外，免疫组织化学显示，在用苯妥英和唑尼沙胺治疗的小鼠中，含有CD4和CD8抗原的肿瘤浸润淋巴细胞减少。两种抗惊厥药物，苯妥英和唑尼沙胺，在小鼠胶质瘤模型中对CLN淋巴细胞的IFN-γ产生显示出显著抑制作用，尽管对照组和抗惊厥药物治疗组小鼠的MST差异无统计学意义。当这些药物与荷瘤状态伴随的潜在免疫功能障碍相结合时，可能会对脑肿瘤患者的预后产生一些不利影响。
