AMINOPEPTIDASE INHIBITOR UBENIMEX (BESTATIN) INHIBITS THE GROWTH OF HUMAN CHORIOCARCINOMA IN NUDE-MICE THROUGH ITS DIRECT CYTOSTATIC ACTIVITY

Ubenimex (bestatin), a potent inhibitor of amino-peptidases, is known to have immunomodulatory and host-mediated antitumor activities. In th is paper, we investigated the inhibitory effects of bestatin on the gr owth of human choriocarcinoma both in vitro and in vivo wing the estab lished choriocarcinoma cell line NaUCC-4. Bestatin inhibited the in vi tro proliferation of NaUCC-4 cells concentration- and time-dependently at more than 72 h incubation. DNA histograms by flow cytometric analy sis revealed that exposure to bestatin at 5 to 20 mu g/ml for 72 h cau sed 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 cycl e. In vivo antitumor activity of bestatin was examined using the NaUCC -4 choriocarcinomaxenografted nude mouse mouse. Tumor growth was signi ficantly inhibited by daily i.p. administration of bestatin for 4 week s at doses of 2 and 20 mg/kg (p<0.01 and p<0.001, respectively), but n ot by 0.2 mg/kg as compared with control. No significant augmentaion o f NK activity or B cell mitogenicity in spleen cells taken from these NaUCC-4-bearing nude mice was observed following treatment with bestat in at either 2 or 20 mg/kg. These results indicate that bestatin inhib its the growth of NaUCC-4 choriocarcinoma in vivo as well as in vitro not via potentiation of effector cells but I rather by its direct cyto static activity, and suggest that bestatin may have an additional ther apeutic property besides as a BRM for its use in the treatment of chor iocarcinoma.