(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), a novel bis-naphthalimide with potent nonselective tumoricidal activity in vitro.
(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.
Kirshenbaum
M R
MR
Research and Development Department, Du Pont Merck Pharmaceutical Company, Glenolden, Pennsylvania 19036.
Chen
S F
SF
Behrens
C H
CH
Papp
L M
LM
Stafford
M M
MM
Sun
J H
JH
Behrens
D L
DL
Fredericks
J R
JR
Polkus
S T
ST
Sipple
P
P
D000677:Amsacrine / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D003110:Colonic Neoplasms; D003609:Dactinomycin / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007546:Isoquinolines / Q000633:toxicity*; D007624:KB Cells; D007700:Kinetics; D007930:Leucine / Q000378:metabolism; D007939:Leukemia L1210; D007941:Leukemia P388; D008325:Mammary Neoplasms, Experimental; D008545:Melanoma; D008546:Melanoma, Experimental; D008698:Mesylates / Q000633:toxicity*; D051379:Mice; D008942:Mitoxantrone / Q000633:toxicity; D013936:Thymidine / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014529:Uridine / Q000378:metabolism
D000970:Antineoplastic Agents; D007546:Isoquinolines; D008698:Mesylates; D000677:Amsacrine; D003609:Dactinomycin; C084899:bisnafide; D004317:Doxorubicin; D008942:Mitoxantrone; D007930:Leucine; D013936:Thymidine; D014529:Uridine