STIMULATION OF IRON(II) BLEOMYCIN ACTIVITY BY PHOSPHATE-CONTAINING COMPOUNDS

Orthophosphate and phosphate derivatives including pyrophosphate, hexametaphosphate, ATP, ADP and inositol hexaphosphate enhance the extent of DNA degradation by iron(II) bleomycin [a glycopeptide antitumor antibiotic]. These phosphate-containing compounds increase both the release of free nucleic base and that of base propenals which are DNA cleavage products, probably by enhancing the efficiency with which Fe(II) is recruited into the drug. Phosphate action occurs during drug activation prior to the attack on DNA. In addition, phosphates affect the stability of the activated drug complex, overcome the inhibition observed with high concentrations of DNA, and reduce the size of the DNA fragment necessary for reacting with the drug. Phosphate derivatives bind to iron(II) bleomycin and alter its optical spectrum. An analysis of titration data for pyrophosphate and inositol hexaphosphate indicates that each phosphate compound binds to > 1 iron(II) bleomycin molecule. With ATP, ADP and 2,3-diphosphoglycerate, only a single phosphate-containing compound binds to the ferrous drug complex. The affinity for ATP is sufficiently hig as to suggest that the ternary complex formed in vitro may exist physiologically.