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Internucleosomal Cleavage and Chromosomal Degradation by Bleomycin and Phleomycin in Yeast¹

Department of Radiation Biology and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642; and Department of Microbiology, Medical School, and Biochemistry and Biology Graduate Programs, City University of New York, New York, New York 10031

Native chromosomal structure, breakage, and overall degradation were studied following the reaction of whole cells with the anticancer drug bleomycin and structurally related phleomycin. Electrophoretic analyses of cellular DNA established that phleomycin was more reactive with DNA than equimolar bleomycin in the range of 0.67-33 x 10^-6 M, produced an optimally visible, though less-extended, oligonucleosomal series at concentrations 12 to 35 times lower than bleomycin, and degraded DNA within nucleosomes. Chromosomes were cleaved into nucleosomes and degraded by phleomycin over substantially narrower dose ranges (1 to 2 x 10^-6 M) than by bleomycin (about 1 to 17 x 10^-5 M). Bleomycin exhibited higher specificity for internucleosomal cleavage than phleomycin, and trimmed but did not degrade nucleosomes at 3 x 10^-5 M. Identical nucleosomal repeat sizes (166 ± 3.8 base pairs) were produced by the analogues. The higher reactivity of phleomycin does not result solely from its higher rate of internucleosomal and intranucleosomal chromatin cleavage, since short phleomycin reactions always resulted in more extensive chromatin cleavage than long bleomycin reactions at low concentrations. In vivo (cellular) repair of chromatin damage was comparable (approximately 90% in 1 h) after cells were exposed to low drug concentrations which produced similar numbers of chromatin breaks, and thus also does not account for the higher chromosomal breakage caused by phleomycin than bleomycin at low doses. At high doses, unrepaired breaks are substantially higher after phleomycin treatments than after bleomycin treatments, and thus contribute to the higher lethal effects of phleomycin than bleomycin.

¹ This study was supported by the National Institutes of Health (Grant CA25609, Department of Health and Human Services), United Cancer Council, Inc. (Rochester), American Cancer Society, Inc. (IN18; New York, NY), contract DE-AC02-76EVO3490 with the U.S. Department of Energy at the University of Rochester Department of Radiation Biology and Biophysics, and The City University of New York Medical School and City College.

² To whom requests for reprints should be addressed, at Department of Microbiology, City University of New York Medical School, Science Building, Room 910, Convent Avenue at 138th Street, New York, NY 10031.

Received 1/11/88. Revised 6/29/88. Revised 8/25/88. Accepted 8/31/88.

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