Characterization of the biological and biochemical activities of F 11782 and the bisdioxopiperazines, ICRF-187 and ICRF-193, two types of topoisomerase II catalytic inhibitors with distinctive mechanisms of action

F11782 is a newly identified catalytic inhibitor of topoisomerases I and II , without any detectable interaction with DNR. This study aimed to establis h whether its catalytic inhibition of topoisomerase II was mediated by mech anisms similar to those identified for the bisdioxopiperazines. In vitro co mbinations of F 11782 with etoposide resulted in greater than additive cyto toxicity in L1210 cells, contrasting with marked antagonism for combination s of etoposide with either ICRF-187 or ICRF-193. All three compounds caused a G(2)/M blockade of P388 cells after an 18-h incubation, but by 40 h poly ploidization was evident only with the bisdioxopiperazines. Gel retardation data revealed that only F 11782, and not the bisdioxopiperazines, was capa ble of completely inhibiting the DNA-binding activity ed topoisomerase II, confirming its novel mechanism of;action. Furthermore, unlike ICRF-187 and ICRF-193, the cytotoxicity of F 11782 appeared mediated, at least partially , by DNA damage induction in cultured GCT27 human teratoma cells, as judged by a fluorescence-enhancement assay and monitoring p53 activation. Finally , the major in vivo antitumor activity of F 11782 against the murine P388 l eukemia (i.v. implanted) and the B16 melanoma (s.c. grafted) contrasted wit h the bisdioxopiperazines' general lack of activity. overall, F 11782 and t he bisdioxopiperazines appear to function as quite distinctive catalytic to poisomerase II inhibitors. [(C) 2000 Lippincott Williams & Wilkins.].