BINDING OF METALLOBLEOMYCIN TO SYNTHETIC DNA

Medical College Of Wisconsin, Milwaukee WI

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Abstract

Among the agents used to treat human cancer, at least three require metals for their activity, i.e., cis-diamminedichloro Pt(II), bleomycin (Blm), and adriamycin. Of the three, Blm has the most elaborate structure and most complicated chemistry. Blm causes double-strand scission in cells and, because double-strand scission is correlated with inhibition of cell proliferation and is poorly repaired, this type of DNA damage is likely to be responsible for anticancer properties of this compound. In 1997, a new project with graduate student C. Xia was initiated. ESR spectra over time for O2 Co(II) Blm bound to 10-mers with a specific GC binding site or a nonspecific AT binding site were obtained to determine the viability of the O2 Co(II) Blm-DNA adduct for NMR studies. It was found that the half-like for the conversion of O2 Co(II) Blm to H O2 Co(III) Blm is days under our conditions. This reaction corresponded with a change from fast-exchanage data to slow-exchange data from the NMR studies. A second EPR study with graduate student Chunwu Xia was completed to follow the time course of the cyanide adduct of Fe(III) Blm, NC-Fe(III) Blm, upon addition of 10-mers with specific and nonspecific binding sites for FeBlm. Cyanide was slowly released upon binding drug to the 10-mer with the specific, GC, binding site as determined by formation of the low-spin ESR signal for Fe(III) Blm bound toDNA. The low-spin signal did not form over time upon addition of the nonspecific, AT, 10-mer to NC-Fe(III) Blm. Since Fe(III) Blm bound to DNA can bind nitric oxide, carbon monoxide, and hydrogen peroxide, it is not clear why cyanide is released upon binding of the specific, GC, 10-mer.[unreadable]