BIOCHEMICAL-CHARACTERIZATION OF ELSAMICIN AND OTHER COUMARIN-RELATED ANTITUMOR AGENTS AS POTENT INHIBITORS OF HUMAN TOPOISOMERASE-II

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.