Linked Life Data

15542779

Source:http://linkedlifedata.com/resource/pubmed/id/15542779

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2004-11-15
pubmed:abstractText
Targeting topoisomerase II (topo II) is regarded as an important component of the pleiotropic mechanism of action of anthracycline drugs. Here, we show that 4-demethoxy analogues of doxorubicin, including annamycin, exhibit a greater ability to trap topo II cleavage complexes than doxorubicin and some other 4-methoxy analogues. In leukemic CEM cells with wild-type topo II, annamycin induced substantial levels of topo II-mediated DNA-protein cross-links (15-37% of total DNA for 0.5-50 micromol/L drug), whereas doxorubicin-induced DNA-protein cross-links were marginal (0-4%). In CEM/VM-1 cells that harbor mutated, drug-resistant topo II, both 4-methoxy and 4-demethoxy drugs produced marginal DNA-protein cross-links. Annamycin, but not doxorubicin, formed topo II-mediated DNA-protein cross-links also in isolated CEM nuclei. In disparity with the unequal DNA-protein cross-link induction, both drugs induced comparable levels of DNA strand breaks in CEM cells. Compared with CEM, drug cytotoxicity against CEM/VM-1 cells was reduced 10.5- to 13.8-fold for 4-demethoxy analogues but only 3.8- to 5.5-fold for 4-methoxy drugs. Hence, growth inhibition by 4-demethoxy analogues seems more dependent on the presence of wild-type topo II. The enhanced topo II targeting by 4-demethoxy analogues was accompanied by a profound induction of apoptotic DNA fragmentation in leukemic CEM cells. Normal WI-38 fibroblasts, however, were markedly more resistant to annamycin-induced DNA-protein cross-links, apoptosis, and growth inhibition. The enhanced topo II targeting by 4-demethoxy doxorubicin analogues underscores the mechanistic diversity of anthracycline drugs. This diversity needs to be recognized as a factor in responses to drugs such as annamycin and doxorubicin.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1535-7163
pubmed:author
pubmed:issnType
Print
pubmed:volume
3
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1403-10
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Enhanced topoisomerase II targeting by annamycin and related 4-demethoxy anthracycline analogues.
pubmed:affiliation
Department of Radiation Oncology, University of Texas Health Science Center, San Antonio, TX 78245, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't