title: DNA strand scission by the novel antitumor antibiotic leinamycin.
abstract: 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 degrees C and thermal treatment of the leinamycin-DNA adduct released a chemically modified leinamycin from the complex. The lack of cytotoxicity and DNA-cleaving activity for S-deoxyleinamycin indicates that the 1,3-dioxo-1,2-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.
authors.affiliation: Tokyo Research Laboratories, Kyowa Hakko Kogyo Ltd., Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hara
authors.forename: Y
authors.initials: Y
authors.lastname: Saitoh
authors.forename: H
authors.initials: H
authors.lastname: Nakano
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000302:isolation & purification / Q000494:pharmacology*; D001407:Bacillus / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D004249:DNA Damage; D004269:DNA, Bacterial / Q000096:biosynthesis / Q000187:drug effects*; D004277:DNA, Single-Stranded / Q000096:biosynthesis / Q000187:drug effects; D004229:Dithiothreitol / Q000494:pharmacology; D007769:Lactams; D018942:Macrolides; D013302:Streptomyces / Q000032:analysis*; D013844:Thiazoles; D013871:Thiones
chemical_list: D000903:Antibiotics, Antineoplastic; D004269:DNA, Bacterial; D004277:DNA, Single-Stranded; D007769:Lactams; D018942:Macrolides; D013844:Thiazoles; D013871:Thiones; C059000:leinamycin; D004229:Dithiothreitol