Indenoisoquinolines are topoisomerase (Top) I inhibitors developed to overcome 
some of the limitations of camptothecins and expand their anticancer spectrum. 
Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}-propane 
bis(trifluoroacetate) (NSC 727357) is a novel dimeric indenoisoquinoline 
derivative with potent antiproliferative activity in the NCI-60 cell line panel, 
promising hollow fiber activity (score of 32) and activity against xenografts. 
Submicromolar concentrations of the bisindenoisoquinoline NSC 727357 induce Top1 
cleavage complexes at specific sites in biochemical assays. At higher 
concentrations, inhibition of Top1 catalytic activity and DNA intercalation is 
observed. NSC 727357 also induces a limited number of Top2-DNA cleavage 
complexes. In contrast to the effect of other Top1 inhibitors, cells treated 
with the bisindenoisoquinoline NSC 727357 show an arrest of cell cycle 
progression in G(1) with no significant inhibition of DNA synthesis after a 
short exposure to the drug. Moreover, unlike camptothecin and the 
indenoisoquinoline MJ-III-65 (NSC 706744, 
6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-5,11-diketo-2,3-dimethoxy-(methylenedioxy)-11H-indeno[1,2-c]isoquinoline 
hydrochloride), the cytotoxicity of bisindenoisoquinoline NSC 727357 is only 
partially dependent on Top1 and p53, indicating that this drug has additional 
targets besides Top1 and Top2.