In vitro and in vivo pharmacological characterizations of the antitumor properties of two new olivacine derivatives, S16020-2 and S30972-1

S16020-2, a new olivacine derivative and a topoisomerase II inhibitor, has recently entered clinical trials. New analogues and derivatives have been s ynthesized from the S16020-2 compound, Preliminary data indicate that S3097 2-1, one of these S16020-2 derivatives, may exhibit a comparatively higher level of antitumor potency associated with an improved therapeutic index th an does S16020-2, The antitumor activities of S16020-2 and S30972-1 were th erefore characterized both in vitro and in vivo, with Adriamycin and etopos ide chosen as reference compounds. The in vitro data show that S30972-1 is a topoisomerase II inhibitor, mediating its activity through an ATP-depende nt mechanism such as S16020-2, The two olivacine derivatives exhibited simi lar activities in vitro at the levels of the global growth of six human can cer cell lines, of the induction of apoptosis, and of the G(2) cell cycle p hase arrest. The in vivo antitumor activity characterization included the u se of two murine leukemia types (P388-LEU and L1210-LEU), two murine lympho ma-like models (P388-LYM and L1210-LYM), two mammary adenocarcinomas (MXT-H I and MXT-HS), and one melanoma (B16). The data show that S30972-1 is actua lly more efficient in vivo than S16020-2, a feature that may relate to the fact that S30972-1 is less toxic than S16020-2, The S30972-1 compound exhib ited in vivo a level of antitumor activity that was also actually higher th an that exhibited by Adriamycin and similar to that exhibited by etoposide.