Source:http://linkedlifedata.com/resource/pubmed/id/16275994
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
11
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| pubmed:dateCreated |
2005-11-8
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| pubmed:abstractText |
Psorospermin is a natural product that has been shown to have activity against drug-resistant leukemia lines and AIDS-related lymphoma. It has also been shown to alkylate DNA through an epoxide-mediated electrophilic attack, and this alkylation is greatly enhanced at specific sites by topoisomerase II. In this article, we describe the synthesis of the two diastereomers of O5-methyl psorospermin and their in vitro activity against a range of solid and hematopoietic tumors. The diastereomeric pair (+/-)-(2'R,3'R) having the naturally occurring enantiomer (2'R,3'R) is the most active across all the cell lines and shows approximately equal activity in both drug-sensitive and drug-resistant cell lines. In subsequent studies using all four enantiomers of O5-methyl psorospermin, the order of biological potency is (2'R,3'R) > (2'R,3'S) = (2'S,3'R) > (2'S,3'S). This order of potency is also found in the topoisomerase II-induced alkylation of O5-methyl psorospermin and can be rationalized by molecular modeling of the psorospermin-duplex binding complex. Therefore, this study defines the optimum stereochemical requirements for both the topoisomerase II-induced alkylation of DNA and the biological activity by psorospermin and its O5-methyl derivatives. Finally, (2'R,3'R) psorospermin was found to be as effective as gemcitabine in slowing tumor growth in vivo in a MiaPaCa pancreatic cancer model. In addition, (2'R,3'R) psorospermin in combination with gemcitabine was found to show an at least additive effect in slowing tumor growth of MiaPaCa.
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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/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/DNA Topoisomerases, Type II,
http://linkedlifedata.com/resource/pubmed/chemical/Deoxycytidine,
http://linkedlifedata.com/resource/pubmed/chemical/Epoxy Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Xanthones,
http://linkedlifedata.com/resource/pubmed/chemical/gemcitabine,
http://linkedlifedata.com/resource/pubmed/chemical/psorospermin
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| pubmed:status |
MEDLINE
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| pubmed:month |
Nov
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| pubmed:issn |
1535-7163
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| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
4
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
1729-39
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| pubmed:dateRevised |
2007-11-14
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| pubmed:meshHeading |
pubmed-meshheading:16275994-Animals,
pubmed-meshheading:16275994-Antineoplastic Combined Chemotherapy Protocols,
pubmed-meshheading:16275994-Body Weight,
pubmed-meshheading:16275994-Cell Line,
pubmed-meshheading:16275994-Cell Line, Tumor,
pubmed-meshheading:16275994-DNA,
pubmed-meshheading:16275994-DNA Topoisomerases, Type II,
pubmed-meshheading:16275994-Deoxycytidine,
pubmed-meshheading:16275994-Drug Screening Assays, Antitumor,
pubmed-meshheading:16275994-Epoxy Compounds,
pubmed-meshheading:16275994-Inhibitory Concentration 50,
pubmed-meshheading:16275994-Leukemia,
pubmed-meshheading:16275994-Lymphoma,
pubmed-meshheading:16275994-Mice,
pubmed-meshheading:16275994-Mice, Nude,
pubmed-meshheading:16275994-Models, Chemical,
pubmed-meshheading:16275994-Models, Molecular,
pubmed-meshheading:16275994-Pancreatic Neoplasms,
pubmed-meshheading:16275994-Stereoisomerism,
pubmed-meshheading:16275994-Time Factors,
pubmed-meshheading:16275994-Xanthones
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| pubmed:year |
2005
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| pubmed:articleTitle |
Determination of the importance of the stereochemistry of psorospermin in topoisomerase II-induced alkylation of DNA and in vitro and in vivo biological activity.
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| pubmed:affiliation |
The University of Texas at Austin, USA.
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| pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, U.S. Gov't, P.H.S.,
Research Support, N.I.H., Extramural
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