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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
11
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pubmed:dateCreated |
1990-6-14
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pubmed:abstractText |
The effect of combinations of the anthracycline aclarubicin and the topoisomerase II targeting drugs 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucopyra noside) (VP-16) and 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) was investigated in a clonogenic assay. The cytotoxicity of VP-16 was almost completely antagonized by preincubating cells with nontoxic concentrations of aclarubicin. The inhibition of cytotoxicity was not seen when the cells were exposed to aclarubicin after exposure to VP-16. The inhibition was significant over a wide range of aclarubicin concentrations (3 nM to 0.4 microM), above which the toxicity of aclarubicin became apparent. A similar effect was seen on the toxicity of m-AMSA. In contrast to aclarubicin, preincubation with Adriamycin did not antagonize the effect of VP-16. With purified topoisomerase II and naked DNA, aclarubicin did not stimulate the formation of cleavable complexes between topoisomerase II and DNA. Aclarubicin concentrations above 1 microM inhibited the baseline formation of cleavable complexes elicited with the enzyme alone. Low (1 to 10 nM) aclarubicin concentrations increased the formation of cleavable complexes obtained with VP-16 and m-AMSA; however, at aclarubicin concentrations above 1 microM an antagonistic effect was obtained. In cells, the m-AMSA- and VP-16-induced, protein-concealed DNA strand breaks were completely inhibitable by aclarubicin preincubation with no synergic dose levels. Our results suggest that aclarubicin inhibits topoisomerase II-mediated DNA cleavage. This inhibition could represent the mechanism of action of the drug and explain the lack of cross-resistance to the classical anthracyclines. The observed antagonism could have consequences for scheduling of aclarubicin with topoisomerase II-active anticancer drugs.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Aclarubicin,
http://linkedlifedata.com/resource/pubmed/chemical/Amsacrine,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Neoplasm,
http://linkedlifedata.com/resource/pubmed/chemical/Doxorubicin,
http://linkedlifedata.com/resource/pubmed/chemical/Etoposide,
http://linkedlifedata.com/resource/pubmed/chemical/Topoisomerase II Inhibitors
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0008-5472
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
50
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3311-6
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:2159380-Aclarubicin,
pubmed-meshheading:2159380-Amsacrine,
pubmed-meshheading:2159380-Carcinoma, Small Cell,
pubmed-meshheading:2159380-Cell Survival,
pubmed-meshheading:2159380-DNA, Neoplasm,
pubmed-meshheading:2159380-DNA Damage,
pubmed-meshheading:2159380-Doxorubicin,
pubmed-meshheading:2159380-Etoposide,
pubmed-meshheading:2159380-Humans,
pubmed-meshheading:2159380-Lung Neoplasms,
pubmed-meshheading:2159380-Topoisomerase II Inhibitors,
pubmed-meshheading:2159380-Tumor Cells, Cultured
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pubmed:year |
1990
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pubmed:articleTitle |
Antagonistic effect of aclarubicin on the cytotoxicity of etoposide and 4'-(9-acridinylamino)methanesulfon-m-anisidide in human small cell lung cancer cell lines and on topoisomerase II-mediated DNA cleavage.
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pubmed:affiliation |
Department of Oncology, Finsen Institute, Copenhagen, Denmark.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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