Linked Life Data

9187272

Source:http://linkedlifedata.com/resource/pubmed/id/9187272

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
1997-7-14
pubmed:abstractText
The role of the site selectivity of topoisomerase II poisoning in the cytotoxic activity of anthracyclines has not been established. In this article, we have thus studied the levels and persistence of double-stranded DNA breaks (DSB) along with the cytotoxic activity in human leukemic HL60 cells of seven anthracyclines, including doxorubicin, daunorubicin, and idarubicin, as well as sugar-modified analogues characterized by an altered sequence specificity. Epimerization at the 3' position of the sugar moiety markedly affected the biological activity; indeed, a dramatic reduction of drug effects was evident for 3'-deamino-3'-epi-hydroxy-4'-deoxy-4'-amino-daunorubicin. The studied analogues could be gathered into three groups based on the DSB/cytotoxicity ratio. At equitoxic concentrations: (a) parent drugs and 3'-deamino-3'-epi-hydroxy-4'-deoxy-4'-amino-daunorubicin endowed with the same sequence specificity stimulated low DSB levels; (b) 3'-epi-daunorubicin and 3'-deamino-4'-deoxy-4'-epi-amino-idarubicin, which have a different sequence specificity, and teniposide (a structurally unrelated poison) stimulated higher amounts of DSB; and (c) 4-demethoxy-3'-deamino-3'-hydroxy-4'-epi-doxorubicin stimulated the highest DSB levels. For the last agent, a faster rate of cleavage resealing, which is consistent with a reduced DNA binding affinity, could account for the increased DSB/cytotoxicity ratio compared with parent drugs. However, for other analogues, the observed differences in DSB persistence/resealing could not completely explain the different DSB/cytotoxicity ratios. The results thus suggest that the cytotoxic potency of anthracyclines may be the result of an interplay of the level, the persistence, and the genomic localization of topoisomerase II-mediated DNA cleavage.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0026-895X
pubmed:author
pubmed:issnType
Print
pubmed:volume
51
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1053-9
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1997
pubmed:articleTitle
Relationship between lethal effects and topoisomerase II-mediated double-stranded DNA breaks produced by anthracyclines with different sequence specificity.
pubmed:affiliation
Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't