Linked Life Data

11439034

Source:http://linkedlifedata.com/resource/pubmed/id/11439034

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
27
pubmed:dateCreated
2001-7-5
pubmed:abstractText
Ecteinascidin 743 (Et 743), one of a series of structurally related antitumor antibiotics isolated from a marine tunicate, is currently in phase II clinical trials. Et 743 alkylates guanine N2 through the minor groove of DNA. Hydrogen-bonding networks that associate the drug with a three base pair DNA recognition site have been proposed to contribute to both the reactivity and the stability of the Et 743-DNA adduct. Here, we report that the reaction of Et 743 with DNA is reversible under nondenaturing conditions and that the rate of this reverse reaction depends critically upon the DNA-modified sequence. Quite unexpectedly, it was found that although the rates of alkylation are similar for the 5'-AGT and 5'-AGC sequences, reversal from the 5'-AGT sequence occurs faster than from the 5'-AGC sequence. Consequently, it is the differences in the rate of the reverse reaction that dictate the sequence selectivity of Et 743 toward its favored target sequence. As a direct consequence of the reversible nature of Et 743 with DNA, Et 743 can migrate from the nonfavored bonding sequence (e.g., 5'-AGT) to the favored DNA target site (e.g., 5'-AGC). The data suggest that the observed differences in the rate of reversibility arise from differences in the stability of the Et 743-DNA adduct at the 5'-AGT and 5'-AGC target sequences. On the basis of gel electrophoresis and (1)H NMR experiments, the Et 743-AGT adduct is less stable, has more dynamic motion, and produces different conformational changes in the DNA than the more stable Et 743-AGC adduct. The shuffling of Et 743-DNA adducts to the more stable alkylation sites has important implications for understanding the underlying relationship between the structural modification of DNA by Et 743 and its biological potency and efficacy in tumor cells.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, Polyomavirus Transforming, http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Alkylating, http://linkedlifedata.com/resource/pubmed/chemical/DNA, http://linkedlifedata.com/resource/pubmed/chemical/DNA Adducts, http://linkedlifedata.com/resource/pubmed/chemical/DNA Helicases, http://linkedlifedata.com/resource/pubmed/chemical/Dioxoles, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Isoquinolines, http://linkedlifedata.com/resource/pubmed/chemical/Nucleic Acid Heteroduplexes, http://linkedlifedata.com/resource/pubmed/chemical/Oligonucleotides, http://linkedlifedata.com/resource/pubmed/chemical/Tetrahydroisoquinolines, http://linkedlifedata.com/resource/pubmed/chemical/trabectedin
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0002-7863
pubmed:author
pubmed:issnType
Print
pubmed:day
11
pubmed:volume
123
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6485-95
pubmed:dateRevised
2008-11-29
pubmed:meshHeading
pubmed:year
2001
pubmed:articleTitle
Differential rates of reversibility of ecteinascidin 743-DNA covalent adducts from different sequences lead to migration to favored bonding sites.
pubmed:affiliation
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, TX 78712, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't