Efficacy of DMP 840: a novel bis-naphthalimide cytotoxic agent with human solid tumor xenograft selectivity.
DMP 840, a novel bis-naphthalimide, was evaluated for antitumor efficacy in several tumor models in mice. As measured by a tumor growth inhibition assay, i.v. administration of DMP 840 to athymic nude mice at doses at or below the maximum tolerated dose resulted in curative activity against four human solid tumor xenografts, MX-1 mammary carcinoma, CX-1 and DLD-2 colon adenocarcinomas, and LX-1 lung carcinoma, producing full or incomplete regressions and/or percent tumor growth inhibition of > or = 96%. The efficacy of DMP 840 in the models was dose dependent. The activity of DMP 840 against the human tumors surpassed that demonstrated by several clinically used and investigational anticancer agents. In long-term growth delay studies, DMP 840 induced full regressions in 20 of 20 mice bearing MX-1 tumors, and tumors in one-half of these mice remained regressed for over 5 months. In addition, DMP 840 was curative against exponentially growing DLD-2 tumors staged at 500 mg and MX-1 tumors staged at 1000 mg. The bis-naphthalimide was equally efficacious when administered i.v. or i.p. but was slightly less active after oral dosing. Against both the MX-1 mammary carcinoma and the DLD-2 colon adenocarcinoma, some measure of schedule dependence was observed; the optimum schedule was daily for 9 days. Against L1210 and P388 murine leukemias, DMP 840 demonstrated little or no activity and was inactive against B16 murine melanoma. Overall, these results suggest that DMP 840 may be a human solid tumor selective cytotoxic agent.
McRipley
R J
RJ
DuPont Merck Pharmaceutical Company, Glenolden Laboratory, Pennsylvania 19036.
Burns-Horwitz
P E
PE
Czerniak
P M
PM
Diamond
R J
RJ
Diamond
M A
MA
Miller
J L
JL
Page
R J
RJ
Dexter
D L
DL
Chen
S F
SF
Sun
J H
JH
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D003110:Colonic Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008698:Mesylates / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007546:Isoquinolines; D008698:Mesylates; C084899:bisnafide