It is known that a number of transition metals (Mn ions, Zn ions, Cd ions, Co ions, and Cu ions) form complexes with the antitumor antibiotic streptonigrin and that the antibiotic associates with DNA in the presence, but not in the absence, of the cations. Certain of the cations (Mn ions, Zn ions, Cd ions) greatly enhanced the bactericidal action of the antibiotic for strains of Escherichia coli. The effects of these transition metals on the following steps that occur in the bactericidal mechanism of streptonigrin will be studied: (1) passage through the membrane; (2) intracellular reduction to the semiquinone or hydroquinone; (3) binding of streptonigrin and its semiquinone to DNA; (4) autoxidation to yield the superoxide anion radical; (5) DNA strand breakage by superoxide. In vivo studies will be carried out on strains of E. coli, including mutants damaged in various DNA repair and recombination functions. In vitro studies will charaterize the nature of the reversible streptonigrin-metal ion-DNA ternary complexes as well as the binary streptonigrin-metal ion complexes. The in vivo studies will be extended to mammalian tissue culture cell lines in order to determine whether the transition metal effects are important in the antitumor activity of streptonigrin.
NIH ExPorter
NIH ExPorter