Linked Life Data

8390259

Source:http://linkedlifedata.com/resource/pubmed/id/8390259

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
1993-7-9
pubmed:abstractText
In contrast to the classic anthracyclines (doxorubicin and daunorubicin), aclarubicin (ACLA) does not stimulate topoisomerase II (topo II) mediated DNA-cleavage. This distinction may be important with respect to topo II-related drug resistance, and the aim of this study was to clarify drug-structures responsible for this difference. Various ACLA analogs were tested for: (a) interaction with purified topo II, (b) induction of DNA cleavage in cells, (c) cellular uptake and (d) cytotoxicity. A remarkable distinction was seen between analogs containing the chromophore aklavinone (AKV) (e.g. ACLA) which have a carboxymethyl group (COOCH3) at C-10 and drugs with a beta-rhodomycinone (RMN) chromophore with hydroxyl groups at C-10 and at C-11. Thus, RMN-containing analogs, including the aglycone RMN itself, effectively stimulated topo II-mediated DNA cleavage. In contrast, AKV-containing drugs inhibited DNA cleavage and antagonized cytotoxicity mediated by RMN-containing drugs. In OC-NYH/VM cells, exhibiting multidrug resistance due to an altered topo II phenotype (at-MDR), cross-resistance was only seen to the RMN-containing drugs whereas no cross-resistance was seen to the non-DNA cleaving AKV-containing compounds. Thus, our data show that one domain in the anthracycline is of particular importance for the interaction with topo II, namely the positions C-10 and C-11 in the chromophore, and further that at-MDR was circumvented by a COOCH3 substitution at position C-10. These findings may provide guidance for the synthesis and development of new analogs with activity in at-MDR cells.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
25
pubmed:volume
45
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2025-35
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:8390259-Aclarubicin, pubmed-meshheading:8390259-Animals, pubmed-meshheading:8390259-Anthracyclines, pubmed-meshheading:8390259-Antibiotics, Antineoplastic, pubmed-meshheading:8390259-Carcinoma, Small Cell, pubmed-meshheading:8390259-DNA, Neoplasm, pubmed-meshheading:8390259-DNA Damage, pubmed-meshheading:8390259-DNA Topoisomerases, Type II, pubmed-meshheading:8390259-Drug Interactions, pubmed-meshheading:8390259-Drug Resistance, pubmed-meshheading:8390259-Drug Screening Assays, Antitumor, pubmed-meshheading:8390259-Humans, pubmed-meshheading:8390259-Leukemia L1210, pubmed-meshheading:8390259-Lung Neoplasms, pubmed-meshheading:8390259-Mice, pubmed-meshheading:8390259-Naphthacenes, pubmed-meshheading:8390259-Stimulation, Chemical, pubmed-meshheading:8390259-Structure-Activity Relationship, pubmed-meshheading:8390259-Topoisomerase II Inhibitors, pubmed-meshheading:8390259-Tumor Cells, Cultured
pubmed:year
1993
pubmed:articleTitle
Different modes of anthracycline interaction with topoisomerase II. Separate structures critical for DNA-cleavage, and for overcoming topoisomerase II-related drug resistance.
pubmed:affiliation
Department of Oncology, Finsen Institute, Rigshospitalet, Blegdamsvej, Denmark.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't