ANTITUMOR-ACTIVITY OF ACTINONIN IN-VITRO AND IN-VIVO

Actinonin, an antibiotic and CD13/aminopeptidase N (APN) inhibitor, ha s been shown to be cytotoxic to tumor cell lines in vitro, We investig ated the antiproliferative effects of actinonin on human and murine le ukemia and lymphoma cells. Actinonin inhibited growth of NB4 and HL60 human cell lines and AKR mouse leukemia cells in vitro with an IC50 of about 2-5 mu g/ml. The inhibitory effect on CD13-positive cells was n ot blocked by pretreatment with the anti-CD13/APN monoclonal antibody F23, which binds with high affinity to the active site of CD13/APN and blocks its enzymatic activity. Moreover, F23 alone was not inhibitory to CD13-positive cells. Furthermore, a similar inhibitory IC50 of act inonin was seen in the CD13-negative cell lines RAJI and DAUDI human l ymphoma. These data suggest that the inhibitory effect of actinonin is not mediated by inhibition of CD13/APN, Cell cycle analysis showed th at actinonin induces a G(1) arrest in HL60 and NB4 cells; apoptosis wa s observed in 20-35% of the cells as measured by intracellular flow cy tometry. To assess whether these effects could be seen in vivo, the ef fect of actinonin on the syngeneic AKR mouse leukemia model was evalua ted. Actinonin showed dose-dependent antitumor effects on AKR leukemia in vivo, resulting in a survival advantage. In conclusion, apoptosis, growth inhibition, and therapeutic effects in vivo are induced by act inonin and are not likely to be mediated by CD13/APN.