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Intracellular DNA Strand Scission and Growth Inhibition of Ehrlich Ascites Tumor Cells by Bleomycins¹

Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201

A comparison of the intracellular DNA strand scission activities of the antitumor drug bleomycin, three of its metal complexes, demethyl bleomycin A₂, and iron-containing, redox-inactivated bleomycin in Ehrlich ascites tumor cells was performed by means of the alkaline elution technique. This comparison was aided by use of CoCl₂ to eliminate or minimize post-cell lysis strand scission by bleomycin in aliquots of treated cultures. No strand scission resulted from treatment of cells with the cobalt complex. The levels of intracellular DNA degradation by copper bleomycin and iron bleomycin were equivalent to those produced by metal-free bleomycin. The findings are correlated with previous measurements of growth inhibition by these three bleomycins as well as by cobalt bleomycin and related to the concentrations of radiolabeled bleomycin bound to DNA after treatment of cells with each form of drug. In comparison, both demethyl bleomycin A₂ and iron-containing, redox-inactivated bleomycin showed marked, concentration-dependent reductions in random DNA strand scission, as compared with unmodified bleomycin or iron bleomycin prepared from Fe(III) and bleomycin. However, the fraction of DNA from cells treated with these two bleomycins, which eluted through filters prior to alkaline denaturation, was equivalent to that for unmodified bleomycin and Fe(III)bleomycin. The generation of this class of damaged DNA correlates more closely with concentration-dependent growth inhibition by each of the six forms of bleomycin than the degree of random strand scission.

¹ Supported by NIH CA-22184.

² Present address: Warner-Lambert Company, Ann Arbor, MI 48104.

³ Present address: Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706.

⁴ Present address: Milwaukee Blood Center, Milwaukee, WI 53226.

⁵ To whom requests for reprints should be addressed, at Department of Chemistry, University of Wisconsin-Milwaukee, Chemistry Building, 3210 N. Cramer Street, Milwaukee, WI 53201.

Received 9/13/89. Revised 4/23/90.

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