Analysis of eukaryotic topoisomerase II cleavage sites in the presence of the quinolone CP-115,953 reveals drug-dependent and -independent recognition elements
The quinolone derivative CP-115,953 [6,8-difluoro-7-(4-hydroxyphenyl)-1-cyclopropyl-4-quinolone-3-carboxylic acid] has been shown to induce eukaryotic topoisomerase II-mediated breaks in DNA, producing cleavage patterns that are distinct from those induced by the anticancer drugs amsacrine, etoposid...
Saved in:
Published in | Molecular pharmacology Vol. 48; no. 2; pp. 238 - 249 |
---|---|
Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.08.1995
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | The quinolone derivative CP-115,953 [6,8-difluoro-7-(4-hydroxyphenyl)-1-cyclopropyl-4-quinolone-3-carboxylic acid] has been
shown to induce eukaryotic topoisomerase II-mediated breaks in DNA, producing cleavage patterns that are distinct from those
induced by the anticancer drugs amsacrine, etoposide, and teniposide. High levels of the quinolone have been found to inhibit
topoisomerase II activity via an interaction with the enzyme and not by DNA unwinding. Topoisomerase II cleavage sites were
analyzed on nine DNA fragments, and 85 quinolone-induced sites were sequenced, as well as 86 amsacrine and 134 teniposide
sites. A consensus sequence was derived for the quinolone sites that is different from those reported for other drugs; however,
because topoisomerase II cleavage sites are double-stranded but not palindromic, different consensus sequences are not easily
compared. For this reason, a new, double-stranded, consensus sequence method, the "unique-base analysis," was developed; this
was applied to the quinolone sites as well as six other large sets of topoisomerase II sites determined in the absence or
presence of drugs. For each of the seven sets of sites, conserved bases were found in the 16-base region spanning positions
-6 to +10, relative to the enzyme cleavage site (DNA breakage between -1 and +1). The conserved bases were virtually identical
in the regions flanking the cleavage site for all seven data sets. In contrast, the base preferences identified proximal to
the cleavage sites were unique to the drug tested. These observations suggest that the selection of cleavage sites by topoisomerase
II involves both enzyme-dependent and drug-dependent recognition elements. The single most preferred base in the quinolone
sites was a cytosine at -1; the same preference was found with teniposide, and 60 of the 85 quinolone sites co-localized with
teniposide sites. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0026-895X 1521-0111 |