title: Antitumor effect of fibrin glue containing temozolomide against malignant glioma.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Kumamoto University Graduate School of Medical Science, Honjo, Chuo-ku, Kumamoto, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Anai
authors.forename: Takuichiro
authors.initials: T
authors.lastname: Hide
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Takezaki
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Kuroda
authors.forename: Naoki
authors.initials: N
authors.lastname: Shinojima
authors.forename: Keishi
authors.initials: K
authors.lastname: Makino
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakamura
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Yano
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kuratsu
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D015718:Fibrin Tissue Adhesive / Q000008:administration & dosage* / Q000737:chemistry; D005910:Glioma / Q000188:drug therapy*; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000517:prevention & control; D009368:Neoplasm Transplantation; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003692:Delayed-Action Preparations; D015718:Fibrin Tissue Adhesive; D003606:Dacarbazine; D000077204:Temozolomide
keywords: Drug delivery system; fibrin glue; glioblastoma; malignant glioma; temozolomide