Anti-proliferative effects of TNP-470 on human malignant glioma in vivo: potent inhibition of tumor angiogenesis.
A novel angiogenesis inhibitor TNP-470 was investigated for its anti-tumor activity against malignant gliomas both in vitro and in vivo. TNP-470 cytostatically inhibited the growth in all of the seven glioma cell lines in culture including anticancer drug resistant cells. The 50% inhibitory concentrations (IC50) of these glioma cell lines were 10 to 30 micrograms/ml and they were 10 to 20 times higher than IC50 of normal endothelial cells. TNP-470 (30 mg/kg, i.p., every other day) also significantly inhibited the tumor growth of T98G-transplanted nude mice. Microscopically, tumor vessels after the treatment of the tumor-bearing mice with TNP-470 became fewer in number and smaller in diameter than those without treatment. Furthermore, there appeared extensive necrotic areas in the tumor with TNP-470. These results indicate that TNP-470 is a potent angiogenesis inhibitor for malignant gliomas. In addition, the studies of labeling index of BrdU and Ki67 suggest that TNP-470 may act mainly on tumor endothelial cells, thus resulting in reduction of the tumor growth.
Taki
T
T
Department of Neurosurgery, Osaka University Medical School, Japan.
Ohnishi
T
T
Arita
N
N
Hiraga
S
S
Saitoh
Y
Y
Izumoto
S
S
Mori
K
K
Hayakawa
T
T
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D003510:Cyclohexanes; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D051381:Rats; D012717:Sesquiterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol