IS[5-NITRO-1H-BENZ[DE]ISOQUINOLINE-1,3-(2H)-DIONE] DIMETHANESULFONATE(DMP-840), A NOVEL BIS-NAPHTHALIMIDE WITH POTENT NONSELECTIVE TUMORICIDAL ACTIVITY IN-VITRO

is[5-nitro-1H-benz[de]isoquinoline-1,3-(2H)-dione] dimethanesulfonate (DMP 840), is a bis-naphthalimide anticancer tumoricidal agent current ly in phase I clinical trials. DMP 840 exhibits curative activity in h uman tumor xenografts, where it shows selectivity for human solid tumo rs over murine leukemias. In contrast to the selectivity found for DMP 840 in vivo, DMP 840 exhibits potent antiproliferative activity in vi tro against a variety of human and murine leukemia and solid tumor cel l lines in culture, with inhibitory doses that reduce the number of tr eated cells to one half (IC50) values ranging from 2.3 to 53 nM. DMP 8 40 was growth inhibitory to three doxorubicin-resistant cell lines wit h IC50 values also in the nanomolar range. Clonogenic survival experim ents showed that DMP 840 was equally cytotoxic to both exponentially g rowing and quiescent human clone A colon carcinoma cells. A 1-h incuba tion of DMP 840 (1.22-12 mu M) 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 s urvival experiments and initial mechanism of action studies was consis tent with a DNA-interactive mechanism for DMP 840 cytotoxicity. Mechan ism of action studies in L1210 leukemia cells demonstrated that DMP 84 0 inhibited the incorporation of thymidine and uridine into DNA and RN A with IC50 values of 0.55 and 0.08 mu M, respectively. DMP 840 produc ed DNA single-strand breaks in a dose-dependent manner. Double-strand breaks were not observed with DMP 840 treatment, even at higher concen trations of compound. Chinese hamster ovary (CHO) and P388 cells resis tant to camptothecin and containing a mutant form of topoisomerase I w ere also used to evaluate whether DMP 840 was cross-resistant with age nts active against topoisomerase I. While the CHOR line was 163-fold r esistant to camptothecin, the CHOR line was only 1.7-fold resistant to DMP 840. In summary, DMP 840 is a DNA-interactive agent that demonstr ates excellent antiproliferative activity in vitro against cultured tu mor cells from both human and murine sources. Its mechanism of tumoric idal activity may be novel.