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Cleavage of Cellular and Extracellular Saccharomyces cerevisiae DNA by Bleomycin and Phleomycin¹

Department of Microbiology, Medical School, and Biochemistry and Biology Graduate Programs, City University of New York, New York, New York 10031

Low-molecular-weight phleomycin (M_r 1500–1600) is considerably less active on a per mol basis than structurally related bleomycin in degrading purified Saccharomyces cerevisiae DNA. Phleomycin also exhibits a substantially higher requirement than bleomycin for ferrous ions. However, phleomycin (0.13 to 3.3 x 10^-6 M) produced 7 to 350 times more breaks than bleomycin in prelabeled intracellular [2-¹⁴C]DNA and [6-³H]DNA and is considerably more cytotoxic than bleomycin. Phleomycin and bleomycin produced equivalent numbers of DNA breaks at equivalent, physiologically meaningful levels of survival, indicating that DNA breaks are related to lethal properties of the anticancer glycopeptides. Phleomycin degradation of extracellular DNA was only detectable at 1.7 x 10^-4 M, approximately two orders of magnitude higher than the concentrations of phleomycin which yielded equivalent fragmentation of intracellular DNA, indicating that phleomycin causes substantially more degradation of intracellular DNA than extracellular DNA. In contrast, bleomycin (1.7 x 10^-5 M) degradation of purified DNA is quite extensive and considerably greater than the degradation of DNA in cells incubated with the same or higher concentrations of bleomycin. Neither phleomycin nor bleomycin cleaved extracellular DNA in the absence of ferrous ions, although both chemical analogues cleaved intracellular DNA without adding iron. Therefore, the requirement for metal ion in stimulating DNA degradation by the two structural families of glycopeptidic antibiotics is met by the cell itself.

¹ This study was supported by the NIH (Grant CA25609, Department of Health and Human Services); United Cancer Council, Inc. (Rochester, NY); American Cancer Society, Inc. (Grant IN18; New York, NY); Contract DEAC02-76EVO3490 with the United States Department of Energy at the University of Rochester, Department of Radiation Biology and Biophysics; The Aaron Diamond Foundation, New York, NY; and the City University of New York Medical School and City College.

² Part of this study was conducted at the Department of Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.

Received 1/30/89. Revised 5/12/89. Revised 8/23/89. Accepted 8/29/89.