Bifunctional intercalation of antitumor antibiotics BBM-928A and echinomycin with DNA. Effects of intercalation on DNA degradative activity of bleomycin and phleomycin

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Abstract
The binding of peptide antitumor antibotics, BBM-928A and echinomycin, to superhelical [bacteriophage] PM2 DNA and the effects of the resulting conformational changes of DNA on the DNA-degradative activity of 2 related antitumor antibiotics, bleomycin A2 and phleomycin D1, were studied. The bifunctional intercalative mode of the DNA binding of BBM-928A concluded previously from viscometric and fluorometric studies was confirmed by gel electrophoretic analysis. Under the employed electrophoretic conditions, DNA-bound BBM-928A showed little dissociation; echinomycin and ethidium bromide showed partial and nearly complete dissociation, respectively. BBM-928A did not induce single-strand or double-strand breaks in DNA. Competitive binding studies by fluorescence changes suggested that binding sites on DNA molecules for BBM-928A or echinomycin may differ from those for ethidium bromide, since binding to DNA by the 2 drugs was not competitive even at saturating concentrations. The lack of such a competition between the 2 drugs is not consistent with the neighbor-exclusion principle. The DNA-degradative activity of bleomycin A2 and phleomycin D1 increased with the removal of the negative superhelicity of DNA by the BBM-928A intercalation and decreased with the formation of positive superhelical turns induced by high concentrations of BBM-928A. Thus, the degradative activity of bleomycin A2 and phleomycin D1 is sensitive in a similar manner to the degree of superhelicity rather than the double helicity of DNA, although there are differences between these 2 drugs in interaction with DNA.