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In Vivo Site Specificity and Human Isoenzyme Selectivity of Two Topoisomerase II-poisoning Anthracyclines¹

Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan [M. B., R. F., E. B., G.C.], and G. Moruzzi Department of Biochemistry, Bologna University, 40126 Bologna [G. C.], Italy

Anthracyclines exert antitumor activity by stimulating site-selective DNA cleavage by topoisomerase II (top2). DNA cleavage sites stimulated by two anthracycline analogues, dh-EPI and da-IDA, were investigated at the histone gene cluster of cultured Drosophila Kc cells. The two agents stimulated analogue-specific patterns of double-stranded DNA cleavage in Kc cell chromatin. Analyses of 47 base sequences of dh-EPI sites showed that the analogue largely followed the in vitro selectivity rule, the requirement of ^5'TA at 3' ends of cleaved strands. da-IDA was more selective than dh-EPI, and thus fewer sites could be collected. Nevertheless, base sequences were consistent with its in vitro base preferences. DNA cleavage was then studied in vitro with Drosophila and human top2 isoforms. The tested drugs stimulated distinct in vitro patterns that corresponded to the in vivo patterns. Human top2 promoted cleavage patterns that were much more similar to those of Drosophila top2 (both in vitro and in vivo) than human top2ß. Moreover, da-IDA showed a marked site-dependent preference for human top2ß. Thus, DNA site selection in vivo is different for the test anthracyclines, and together with a degree of ß-form specificity, may affect drug activity in human cells.

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