A. Lorico et Bh. Long, BIOCHEMICAL-CHARACTERIZATION OF ELSAMICIN AND OTHER COUMARIN-RELATED ANTITUMOR AGENTS AS POTENT INHIBITORS OF HUMAN TOPOISOMERASE-II, European journal of cancer, 29A(14), 1993, pp. 1985-1991
Elsamicin (EM) is a recently discovered antitumour agent that is struc
turally related to several other compounds displaying anticancer activ
ities, including chartreusin (CT), chrysomycin V (CV) and M (CM), gilv
ocarcin V (GV) and ravidomycin (RM). The biochemical events resulting
in cytotoxicity for most of these compounds have not been clearly eluc
idated. There is some evidence that GV and CT bind to DNA and that GV
is photosensitive, causing DNA damage. Therefore, we investigated the
effects of these chemicals on DNA in cells and on pBR322 plasmid DNA.
Using alkaline elution techniques, we found that all these compounds i
nduced, to a different extent, DNA breakage in the human lung adenocar
cinoma A549 cell line. In addition, all either bound to or intercalate
d into DNA, as indicated by their ability to alter the electrophoretic
migration of DNA in agarose gels. Using the P4 unknotting assay, EM,
CT, CV, CM, GV and RV were found to be potent inhibitors of the cataly
tic activity of topsisomerase II (topo II). Their potencies were compa
red with the known topo II inhibitors teniposide (VM-26) and doxorubic
in (DX). EM was the most potent with an IC50 of 0.4 mu mol/l followed
in order by CV, GV, and CT. VM-26 was the least potent with an IC50 of
15 mu mol/l. It was concluded from these results that EM, GV, CV, CM
and CT are capable of inhibiting topo II and that EM is the most poten
t inhibitor of topo II yet discovered.