title: Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas.
abstract: Glioblastoma is a highly angiogenic tumor with a dismal prognosis. Temozolomide (TMZ), a methylating agent is one of the most effective chemotherapeutic agents against glioblastoma. To overcome the problem that most of these tumors become resistant to chemotherapeutic regimens within a year, we investigated the antitumor efficacy of metronomic administration of low-dose TMZ in in vitro cell proliferation/cytotoxicity assay and in vivo rat and nude mouse orthotopic glioma model. By in vitro assay, we elucidated that C6/LacZ rat glioma cells were more resistant to metronomic treatment of TMZ than U-87MG human glioblastoma cells and bEnd.3 mouse brain endothelial cells. Compared with the conventional chemotherapeutic regimen of TMZ, we found that frequent administration of TMZ at a low dose (metronomic treatment) markedly inhibited angiogenesis as well as tumor growth in a TMZ-resistant C6/LacZ rat glioma model. In addition, metronomic treatment of TMZ significantly augmented apoptosis of tumor cells in this model. For the TMZ-sensitive U-87MG cells, even with a very low dose of TMZ, which is not effective to reduce tumor mass, the metronomic treatment of TMZ reduced the microvessel density, i.e. angiogenesis, in a nude mouse orthotopic model. In conclusion, for both models, the metronomic treatment of TMZ decreased angiogenesis. Especially, in TMZ-resistant glioma cells, this regimen increased apoptosis of tumor cells and decreased tumor growth. The metronomic treatment of TMZ in orthotopic glioma models demonstrated a successful antiangiogenic effect which can overcome the chemoresistance in conventional TMZ chemotherapy.
authors.affiliation: Department of Neurosurgery, Samsung Medical Center and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Ji Tae
authors.initials: JT
authors.lastname: Kim
authors.forename: Jong-Soo
authors.initials: JS
authors.lastname: Kim
authors.forename: Kwang Won
authors.initials: KW
authors.lastname: Ko
authors.forename: Doo-Sik
authors.initials: DS
authors.lastname: Kong
authors.forename: Chang-Mo
authors.initials: CM
authors.lastname: Kang
authors.forename: Mi Hyun
authors.initials: MH
authors.lastname: Kim
authors.forename: Myung Jin
authors.initials: MJ
authors.lastname: Son
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Song
authors.forename: Hyung-Jin
authors.initials: HJ
authors.lastname: Shin
authors.forename: Dong-Sup
authors.initials: DS
authors.lastname: Lee
authors.forename: Whan
authors.initials: W
authors.lastname: Eoh
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D005910:Glioma / Q000473:pathology* / Q000628:therapy; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide