Linked Life Data

7812964

Source:http://linkedlifedata.com/resource/pubmed/id/7812964

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
1995-2-3
pubmed:abstractText
Antitumor drugs stimulate topoisomerase II-mediated DNA cleavage in a DNA sequence-specific manner. The drug sequence specificity is often very similar among antitumor agents of the same chemical class. In this work, we demonstrate, however, that 3'-epidaunorubicin has a markedly different sequence specificity as compared with the parent drugs daunorubicin and doxorubicin. The analogue stimulates distinct cleavage intensity patterns in agarose and sequencing gels with two different DNA substrates, although its cleaving activity was lower than that of daunorubicin. A statistical analysis of 44 sites specifically stimulated by the analogue showed that a major difference between the analogue and parent drugs was at position -2, where a guanine is highly preferred by the analogue, whereas parent drugs prefer a thymine and exclude instead a guanine. Interestingly, an analogue with no substituents at the 3'-C of the sugar was able to stimulate DNA cleavage at sites stimulated by parent drugs as well as at those stimulated by 3'-epidaunorubicin. In contrast, the presence of a 2'-OH or a 3'-epi-OH in the sugar moiety and the removal of the OH at 9-C of the A ring did not alter the drug site selectivity, in agreement with several other modifications studied previously. DNA binding affinities of studied agents were not related to drug sequence specificity. The data demonstrate a critical role of the 3' position for optimal anthracycline interactions in the ternary complex. The findings, for the first time, establish a clear relationship between a specific drug substituent and base sequence selectivity and indicate putative DNA- and enzyme-interacting domains of the anthracycline molecule.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
55
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
312-7
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1995
pubmed:articleTitle
Change of the sequence specificity of daunorubicin-stimulated topoisomerase II DNA cleavage by epimerization of the amino group of the sugar moiety.
pubmed:affiliation
Division of 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