Department of Neurosurgery, Kumamoto University Graduate School of Medical Science, Honjo, Chuo-ku, Kumamoto, Japan.
Cancer Sci. 2014 May;105(5):583-91. doi: 10.1111/cas.12397. Epub 2014 Apr 19.
Temozolomide (TMZ), used to treat glioblastoma and malignant glioma, induces autophagy, apoptosis and senescence in cancer cells. We investigated fibrin glue (FG) as a drug delivery system for the local administration of high-concentration TMZ aimed at preventing glioma recurrence. Our high-power liquid chromatography studies indicated that FG containing TMZ (TMZ-FG) manifested a sustained drug release potential. We prepared a subcutaneous tumor model by injecting groups of mice with three malignant glioma cell lines and examined the antitumor effect of TMZ-FG. We estimated the tumor volume and performed immunostaining and immunoblotting using antibodies to Ki-67, cleaved caspase 3, LC3 and p16. When FG sheets containing TMZ (TMZ-FGS) were inserted beneath the tumors, their growth was significantly suppressed. In mice treated with peroral TMZ plus TMZ-FGS the tumors tended to be smaller than in mice whose tumors were treated with TMZ-FGS or peroral TMZ alone. The TMZ-FGS induced autophagy, apoptosis and senescence in subcutaneous glioma tumor cells. To assess the safety of TMZ-FG for normal brain, we placed it directly on the brain of living mice and stained tissue sections obtained in the acute and chronic phase immunohistochemically. In both phases, TMZ-FG failed to severely damage normal brain tissue. TMZ-FG may represent a safe new drug delivery system with sustained drug release potential to treat malignant glioma.
替莫唑胺（TMZ）用于治疗胶质母细胞瘤和恶性胶质瘤，可诱导癌细胞发生自噬、凋亡和衰老。我们研究了纤维蛋白胶（FG）作为局部高浓度 TMZ 给药的药物输送系统，旨在预防胶质瘤复发。我们的高效液相色谱研究表明，含有 TMZ 的 FG（TMZ-FG）表现出持续的药物释放潜力。我们通过向三组小鼠注射三种恶性神经胶质瘤细胞系来制备皮下肿瘤模型，并检查 TMZ-FG 的抗肿瘤作用。我们通过 Ki-67、cleaved caspase 3、LC3 和 p16 的抗体进行免疫染色和免疫印迹来评估肿瘤体积。当含有 TMZ 的 FG 片（TMZ-FGS）插入肿瘤下方时，其生长明显受到抑制。在接受口服 TMZ 加 TMZ-FGS 治疗的小鼠中，肿瘤倾向于小于仅接受 TMZ-FGS 或口服 TMZ 治疗的小鼠的肿瘤。TMZ-FGS 诱导皮下神经胶质瘤肿瘤细胞发生自噬、凋亡和衰老。为了评估 TMZ-FG 对正常大脑的安全性，我们将其直接放置在活鼠的大脑上，并在急性和慢性阶段用免疫组织化学对获得的组织切片进行染色。在这两个阶段，TMZ-FG 均未能严重损害正常脑组织。TMZ-FG 可能代表一种具有持续药物释放潜力的安全新型药物输送系统，可用于治疗恶性胶质瘤。
