Studies related to antitumor antibiotics. Part VIII. Cleavage of DNA by streptonigrin analogues and the relationship to antineoplastic activity

Abstract

A group of substituted 5,8-quinolinequinones which exhibit antineoplastic activity and which are structurally related to the antitumor antibiotic streptonigrin induce single strand cleavage of PM2 covalently-closed circular-DNA (ccc-DNA) when reductively activated. The cleavage which is detected by an ethidium fluorescence assay is specifically enhanced by cuprous and ferrous ion and is selectively inhibited by superoxide dismutase (EC-1.15.1.1) and catalase (EC-1.11.1.6), and by free radical seavengers. Independent generation of the superoxide ion by xanthine-xanthine oxidase (EC-1.2.3.2) also cleaves PM2 DNA and a chemical mechanism for the scission process induced by the streptonigrin analogs is formulated. A correlation between rate of PM2 ccc-DNA cleavage and inhibition of [rat] Walker carcinosarcoma 256 is observed.