Differential in vitro interactions of a series of clinically useful topoisomerase-interacting compounds with the cleavage/religation activity of the human topoisomerase II alpha and II beta isoforms

The topoisomerase II (TOP2)-associated DNA cleavage activity and the DNA se quence preference of 20 antitumor drugs, including 15 TOP2-interacting comp ounds, have been defined. Four major classes of drugs have been identified: (i) those which enhanced the stabilization of cleavable complexes at a sin gle major site (e.g. amsacrine, doxorubicin), or (ii) at many sites (e.g. e toposide, azatoxin), with chemically related compounds having very similar, although not identical, cleavage patterns (e.g. etoposide, GL331 and Top-5 3); (iii) those which inhibited DNA breakage (e.g. aclarubicin, actinomycin D); and (iv) those which did not visibly interfere with TOPS-mediated clea vable complexes (e.g. ICRF-187, camptothecin). All drugs tested induced sim ilar overall patterns of sites of preferred DNA cleavage, in the presence e ither of the two known isoforms, TOP2 alpha or TOP2 beta, although relative intensities of signals at each position varied. It has been further shown that etoposide and its derivatives blocked the religation step downstream o f the DNA cleavage step, whereas amsacrine, ellipticine, azatoxin and genis tein acted upstream through enhancement of DNA cleavage. The information pr ovided by this mechanistically based comparison can now be exploited in des igning or synthesizing novel TOP2-interacting agents. [(C), 1999 Lippincott Williams & Wilkins.].