DNA damage and cytotoxicity in L1210 cells by ellipticine and a structural analogue, N-2-(diethylaminoethyl)-9-hydroxyellipticinium chloride.

Abstract

N-2-(Diethylaminoethyl)-9-hydroxyellipticinium chloride (DHE) is a structural analogue of ellipticine that is currently a leading compound for clinical trials. We have investigated the mechanism of DNA damage by this compound in murine L1210 leukemia cells using the method of alkaline elution. Although DHE was about 100-fold more cytotoxic than ellipticine, this increased cytotoxicity was not accompanied by greater amounts of DNA strand breakage or protein-DNA cross-linking. The single strand breaks caused by both compounds were protein associated and could be accounted for by the presence of double strand breaks. DNA damage by the compounds therefore was consistent with topoisomerase II inhibition. Unlike DHE, 80% of the DNA damage elicited by ellipticine was repaired within 1 h after removal of drug. For DHE, 20-h incubations in drug-free media were required to obtain 70% repair of single strand DNA breaks. These data indicated that although both ellipticine and DHE may inhibit topoisomerase II, the type of DNA damage which resulted in topoisomerase II inhibition by DHE was much more persistent than the DNA damage elicited by ellipticine.