DNA STRAND SCISSION BY THE NOVEL ANTITUMOR ANTIBIOTIC LEINAMYCIN

Leinamycin is a recently discovered antitumor antibiotic with an unusual 1,3-dioxo-1,2-dithiolane structure. It preferentially inhibits the incorporation of [3H]thymidine into the acid-insoluble fraction of Bacillus subtilis. In vitro, leinamycin causes single-strand cleavage of supercoiled double-helical pBR322 DNA in the presence of thiol cofactors. Scavengers of oxygen radical did not supress the DNA-cleaving activity. Thiol-activated leinamycin binds calf thymus DNA at 4 °C and thermal treatment of the lein-amycin-DNA adduct released a chemically modified leinamycin from the complex. The lack of cytotoxicity and DNA-cleaving activity for S-deoxyleinamycin indicates that the l,3-dioxo-l,2-dithiolane moiety is essential for the activity of leinamycin. Thus, the primary cellular target of leinamycin appears to be DNA. It binds DNA and causes single-strand break at low concentrations, which may account for the potent antitumor activity. © 1990, American Chemical Society. All rights reserved.