Comparative efficacy of DMP 840 against mouse and human solid tumor models.
BACKGROUND
DMP 840 is a compound from a class of bis-naphthalimide antitumor agents that recently completed Phase I clinical trials at three North American centers and is currently undergoing Phase II testing. Preclinically, it was shown to have curative activity against a variety of human tumor xenograft models.


OBJECTIVE
To test DMP 840 both in vitro and in vivo for antiproliferative activity against predominantly mouse tumor models.


METHODS
A disk diffusion soft agar colony formation assay was used to determine the in vitro growth inhibitory activity against a selection of mouse and human tumor cell lines, and the comparable selective mouse solid tumors were used for in vivo testing.


RESULTS
In vitro DMP 840 exhibited equal cytotoxicity for human tumors (including MX-1 directly cultured from nude mice), mouse tumors and normal 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 02, T/C = 52%; P388/0, 36% ILS (Percent Increased Life Span) and P388/ADR, 14% ILS. Furthermore, the antitumor activity was only observed at the highest non-toxic dose and was associated with a large body weight loss. In contrast, the agent was highly active against the human breast tumor MX-1 implanted subcutaneously 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 tumors was noted. Overall, this compound is rather unique in its differential degree of in vivo activity for human versus mouse tumors.


CONCLUSIONS
Phase II trials, which are ongoing, will help determine if the preclinical in vivo selective activity of DMP 840 translates to clinical activity in man.
LoRusso
P
P
Division of Hematology/Oncology, Wayne State University, Detroit, MI 48201, USA.
Demchik
L
L
Dan
M
M
Polin
L
L
Gross
J L
JL
Corbett
T H
TH
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy; D008698:Mesylates / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007546:Isoquinolines; D008698:Mesylates; C084899:bisnafide