Document Detail


(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.
MedLine Citation:
PMID:  8174127     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
(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.
Authors:
M R Kirshenbaum; S F Chen; C H Behrens; L M Papp; M M Stafford; J H Sun; D L Behrens; J R Fredericks; S T Polkus; P Sipple
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Cancer research     Volume:  54     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1994 Apr 
Date Detail:
Created Date:  1994-06-06     Completed Date:  1994-06-06     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2199-206     Citation Subset:  IM    
Affiliation:
Research and Development Department, Du Pont Merck Pharmaceutical Company, Glenolden, Pennsylvania 19036.
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MeSH Terms
Descriptor/Qualifier:
Amsacrine / toxicity
Animals
Antineoplastic Agents / toxicity*
Cell Division / drug effects
Clinical Trials, Phase I as Topic
Colonic Neoplasms
Dactinomycin / toxicity
Dose-Response Relationship, Drug
Doxorubicin / toxicity
Drug Resistance
Drug Screening Assays, Antitumor
Humans
Isoquinolines / toxicity*
KB Cells
Kinetics
Leucine / metabolism
Leukemia L1210
Leukemia P388
Mammary Neoplasms, Experimental
Melanoma
Melanoma, Experimental
Mesylates / toxicity*
Mice
Mitoxantrone / toxicity
Thymidine / metabolism
Transplantation, Heterologous
Tumor Cells, Cultured
Uridine / metabolism
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Isoquinolines; 0/Mesylates; 145124-30-7/bisnafide; 23214-92-8/Doxorubicin; 50-76-0/Dactinomycin; 50-89-5/Thymidine; 51264-14-3/Amsacrine; 58-96-8/Uridine; 61-90-5/Leucine; 65271-80-9/Mitoxantrone

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