title: Aminopeptidase inhibitor ubenimex (bestatin) inhibits the growth of human choriocarcinoma in nude mice through its direct cytostatic activity.
abstract: Ubenimex (bestatin), a potent inhibitor of aminopeptidases, is known to have immunomodulatory and host-mediated antitumor activities. In this paper, we investigated the inhibitory effects of bestatin on the growth of human choriocarcinoma both in vitro and in vivo using the established choriocarcinoma cell line NaUCC-4. Bestatin inhibited the in vitro proliferation of NaUCC-4 cells concentration- and time-dependently at more than 72 h incubation. DNA histograms by flow cytometric analysis revealed that exposure to bestatin at 5 to 20 micrograms/ml for 72 h caused mild accumulation of NaUCC-4 cells in the G0/G1 phase of the cell cycle, although no clear arrest was observed in any phase of cell cycle. In vivo antitumor activity of bestatin was examined using the NaUCC-4 choriocarcinoma-xenografted nude mouse model. Tumor growth was significantly inhibited by daily i.p. administration of bestatin for 4 weeks at doses of 2 and 20 mg/kg (p < 0.01 and p < 0.001, respectively), but not by 0.2 mg/kg as compared with control. No significant augmentation of NK activity or B cell mitogenicity in spleen cells taken from these NaUCC-4-hearing nude mice was observed following treatment with bestatin at either 2 or 20 mg/kg. These results indicate that bestatin inhibits the growth of NaUCC-4 choriocarcinoma in vivo as well as in vitro not via potentiation of effector cells but rather by its direct cytostatic activity, and suggest that bestatin may have an additional therapeutic property besides as a BRM for its use in the treatment of choriocarcinoma.
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University School of Medicine, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Inoi
authors.forename: S
authors.initials: S
authors.lastname: Goto
authors.forename: S
authors.initials: S
authors.lastname: Nomura
authors.forename: K
authors.initials: K
authors.lastname: Isobe
authors.forename: A
authors.initials: A
authors.lastname: Nawa
authors.forename: T
authors.initials: T
authors.lastname: Okamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Tomoda
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D002822:Choriocarcinoma / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000188:drug therapy*
chemical_list: D000903:Antibiotics, Antineoplastic; D000626:Aminopeptidases; D007930:Leucine; C012211:ubenimex