Bifunctional intercalation of antitumor antibiotics BBM-928A and echinomycin with deoxyribonucleic acid. Effects of intercalation on deoxyribonucleic acid degradative activity of bleomycin and phleomycin.
The binding of peptide antitumor antibiotics, BBM-928A and echinomycin, to superhelical PM2 DNA and the effects of the resulting conformational changes of DNA on the DNA-degradative activity of two related antitumor antibiotics, bleomycin A2 and phleomycin D1, have been studied. The bifunctional intercalative mode of the DNA binding of BBM-928A concluded previously from viscometric and fluorometric studies has been confirmed by gel electrophoretic analysis. Under the employed electrophoretic conditions, DNA-bound BBM-928A showed little dissociation whereas echinomycin and ethidium bromide showed partial and nearly complete dissociation, respectively. BBM-928A induced neither single-strand nor 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 two drugs was not competitive even at saturating concentrations. The lack of such a competition between the two drugs is not consistent with the neighbor-exclusion principle. The DNA-degradative activity of both 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 both 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 two drugs in interaction with DNA.
D000818:Animals; D000903:Antibiotics, Antineoplastic; D001435:Bacteriophages; D001761:Bleomycin; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA; D004277:DNA, Single-Stranded; D004278:DNA, Superhelical; D004279:DNA, Viral; D004448:Echinomycin; D010692:Phleomycins; D011549:Pseudomonas; D011804:Quinolines; D011810:Quinoxalines; D013050:Spectrometry, Fluorescence; D013950:Thymus Gland
D000903:Antibiotics, Antineoplastic; D004277:DNA, Single-Stranded; D004278:DNA, Superhelical; D004279:DNA, Viral; D010692:Phleomycins; D011804:Quinolines; D011810:Quinoxalines; D001761:Bleomycin; D004448:Echinomycin; C027844:BBM-928; D004247:DNA