(R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]
isoquinoline-1,3-(2H)-dione] dimethanesulfonate (
DMP 840), is a bis-
naphthalimide anticancer tumoricidal agent currently in phase I clinical trials.
DMP 840 exhibits curative activity in human
tumor xenografts, where it shows selectivity for human solid
tumors over murine
leukemias. In contrast to the selectivity found for
DMP 840 in vivo,
DMP 840 exhibits potent antiproliferative activity in vitro against a variety of human and murine
leukemia and solid tumor cell lines in culture, with inhibitory doses that reduce the number of treated cells to one half (IC50) values ranging from 2.3 to 53 nM.
DMP 840 was growth inhibitory to three
doxorubicin-resistant cell lines with IC50 values also in the nanomolar range. Clonogenic survival experiments showed that
DMP 840 was equally cytotoxic to both exponentially growing and quiescent human clone A colon
carcinoma cells. A 1-h incubation of
DMP 840 (1.22-12 microM) caused 5-log cell kill in KB-3-1 human
epidermoid carcinoma, clone A human colon
carcinoma, and L1210 murine
leukemia cell lines. The rapid cell killing by
DMP 840 in clonogenic survival experiments and initial mechanism of action studies was consistent with
a DNA-interactive mechanism for
DMP 840 cytotoxicity. Mechanism of action studies in
L1210 leukemia cells demonstrated that
DMP 840 inhibited the incorporation of
thymidine and
uridine into
DNA and
RNA with IC50 values of 0.55 and 0.08 microM, respectively.
DMP 840 produced
DNA single-strand breaks in a dose-dependent manner. Double-strand breaks were not observed with
DMP 840 treatment, even at higher concentrations of compound. Chinese hamster ovary (CHO) and P388 cells resistant to
camptothecin and containing a mutant form of
topoisomerase I were also used to evaluate whether
DMP 840 was cross-resistant with agents active against
topoisomerase I. While the CHOR line was 163-fold resistant to
camptothecin, the CHOR line was only 1.7-fold resistant to
DMP 840. In summary,
DMP 840 is
a DNA-interactive agent that demonstrates excellent antiproliferative activity in vitro against cultured tumor cells from both human and murine sources. Its mechanism of tumoricidal activity may be novel.