COMPARATIVE EFFICACY OF DMP-840 AGAINST MOUSE AND HUMAN SOLID TUMOR-MODELS

Background: DMP 840 is a compound from a class of bis-naphthalimide an titumor agents that recently completed Phase I clinical trials at thre e North American centers and is currently undergoing Phase II testing. Preclinically, it was shown to have curative activity against a varie ty of human tumor xenograft models. Purpose: To test DMP 840 both in v itro and in vivo for antiproliferative activity against predominantly mouse tumor models. Methods: A disk diffusion soft agar colony formati on assay was used to determine the in vitro growth inhibitory activity against a selection of mouse and human tumor cell lines, and the comp arable selective mouse solid tumors were used for in vivo testing. Res ult: In vitro DMP 840 exhibited equal cytotoxicity for human tumors (i ncluding MX-1 directly cultured from nude mice), mouse tumors and norm al cells. In vivo DMP 840 was only modestly active or inactive against the following mouse tumors: Mam 16/C, T/C = 30% (T/C = Percent Tumor Growth Inhibition); Mam 16/C/ADR, T/C = 33%; Colon 38, T/C = 9%; Panc 03, T/C = 53%; Colon 51/A, T/C = 28%; Panc 03 T/C = 52%; P388/0, 36% I LS (Percent Increased Life Span) and P388/ADR, 14% ILS. Furthermore, t he antitumor activity was only observed at the highest non-toxic dose and was associated with a large body weight loss. In contrast, the age nt was highly active against the human breast tumor MX-1 implanted sub cutaneously in either athymic nude or SCID mice (Nudes: T/C = 0%; 1/5 cures; SCIDS: T/C = 0%; 5/5 cures). Conclusions: Although there was no selective cytotoxicity in our clonogenic assay for human versus mouse tumor cell lines, selective activity in vivo for human xenograft tumo rs was noted. Overall, this compound is rather unique in its different ial degree of in vivo activity for human versus mouse tumors. Implicat ions. Phase II trials, which are ongoing, will help determine if the p reclinical in vitro selective activity of DMP 840 translates to clinic al activity in man.