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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
13
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pubmed:dateCreated |
1990-7-23
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pubmed:abstractText |
The cyanomorpholino analog of doxorubicin (MRA-CN) is a potent cytotoxic agent which is known to cross-link DNA. A human ovarian carcinoma cell line, ES-2, was grown in increasing concentrations of MRA-CN from 0.1 to 0.5 nM. The resultant resistant subline, ES-2R, was 4-fold resistant to MRA-CN. DNA damage and repair in response to MRA-CN were compared in the parental and resistant cell lines using alkaline elution. DNA cross-links were detectable after 3-h incubation of the cells at 37 degrees C in MRA-CN at concentrations greater than or equal to 1.0 nM. Paradoxically, 2-fold more cross-links were detected in the ES-2R cells as compared with the ES-2 cells. This paradoxical difference in cross-links between the 2 cell lines was observed to increase with time of exposure to 2.5 nM of MRA-CN. Non-protein-associated DNA strand breaks were also detected in the 2 cell lines after exposure to 2.5 nM of the drug. The ES-2 cells consistently showed twice as many breaks as the ES-2R cells, which could explain the paradoxical higher apparent DNA cross-linking observed with the ES-2R cells after exposure to MRA-CN. Studies of the time course of cross-link repair after exposure to MRA-CN revealed that 75% of the DNA cross-links disappeared in the ES-2R cells by the end of 8 h in drug-free medium. In contrast, cross-links in the ES-2 cells were undetectable after 4 h, which coincided with a progressive increase in DNA strand breaks. The topoisomerase II level in the ES-2 cells was 2- to 4-fold higher than that in the ES-2R cells. However, proteinase K treatment of the lysed cells did not increase the number of apparent strand breaks produced by MRA-CN, suggesting that topoisomerase II may not be involved. These findings indicate that, in addition to DNA cross-linking, MRA-CN causes DNA strand breakage. Resistance to MRA-CN in the ES-2R cells is associated with more apparent DNA cross-linking and less DNA strand breakage, which may be a consequence of differences in DNA repair and/or nonspecific DNA degradation between the resistant and the sensitive cell lines.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/3'-deamino-3'-(3-cyano-4-morpholinyl...,
http://linkedlifedata.com/resource/pubmed/chemical/Cross-Linking Reagents,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Neoplasm,
http://linkedlifedata.com/resource/pubmed/chemical/DNA Topoisomerases, Type II,
http://linkedlifedata.com/resource/pubmed/chemical/Doxorubicin
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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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 |
4056-60
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:2162251-Cross-Linking Reagents,
pubmed-meshheading:2162251-DNA, Neoplasm,
pubmed-meshheading:2162251-DNA Damage,
pubmed-meshheading:2162251-DNA Topoisomerases, Type II,
pubmed-meshheading:2162251-Doxorubicin,
pubmed-meshheading:2162251-Drug Resistance,
pubmed-meshheading:2162251-Female,
pubmed-meshheading:2162251-Humans,
pubmed-meshheading:2162251-Ovarian Neoplasms,
pubmed-meshheading:2162251-Time Factors,
pubmed-meshheading:2162251-Tumor Cells, Cultured
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pubmed:year |
1990
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pubmed:articleTitle |
Paradoxical increase in DNA cross-linking in a human ovarian carcinoma cell line resistant to cyanomorpholino doxorubicin.
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pubmed:affiliation |
Department of Medicine, Stanford University School of Medicine, California 94305-5306.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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