Source:http://linkedlifedata.com/resource/pubmed/id/11479220
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
15
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| pubmed:dateCreated |
2001-7-31
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| pubmed:abstractText |
Thioguanine and mercaptopurine are prodrugs requiring conversion into thiopurine nucleotides to exert cytotoxicity. Thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism, catabolizes thiopurines into inactive methylated bases, but also produces methylthioguanine nucleotides and methylmercaptopurine nucleotides from thioguanine and mercaptopurine nucleotides, respectively. To study the effect of TPMT on activation versus inactivation of mercaptopurine and thioguanine, we used a retroviral gene transfer technique to develop human CCRF-CEM cell lines that did (TPMT+) and did not (MOCK) overexpress TPMT. After transduction, TPMT activities were 14-fold higher in the TPMT+ versus the MOCK cell lines (P < 0.001). TPMT+ cells were less sensitive to thioguanine than MOCK cells (IC(50) = 1.10+/- 0.12 microM versus 0.55 +/- 0.19 microM; P = 0.02); in contrast, TPMT+ cells were more sensitive to mercaptopurine than MOCK cells (IC(50) = 0.52 +/- 0.20 microM versus 1.50 +/- 0.23 microM; P < 0.01). The lower sensitivity of TPMT+ versus MOCK cells to thioguanine was associated with lower thioguanine nucleotide concentrations (917 +/- 282 versus 1515 +/- 183 pmol/5 x 10(6) cells; P = 0.01), higher methylthioguanine nucleotide concentrations (252 +/- 34 versus 27 +/- 10 pmol/5 x 10(6) cells; P = 0.01), less inhibition of de novo purine synthesis (13 versus 95%; P < 0.01), and lower deoxythioguanosine incorporation into DNA (2.0 +/- 0.6% versus 7.2 +/- 2.0%; P < 0.001). The higher sensitivity of TPMT+ cells to mercaptopurine was associated with higher concentrations of methylmercaptopurine nucleotide (2601 +/- 1055 versus 174 +/- 77 pmol/5 x 10(6) cells; P = 0.01) and greater inhibition of de novo purine synthesis (>99% versus 74%; P < 0.01) compared with MOCK cells. We conclude that methylation of mercaptopurine contributes to the antiproliferative properties of the drug, probably through inhibition of de novo purine synthesis by methylmercaptopurine nucleotides, whereas thioguanine is inactivated primarily by TPMT.
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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/6-Mercaptopurine,
http://linkedlifedata.com/resource/pubmed/chemical/6-methylthiopurine,
http://linkedlifedata.com/resource/pubmed/chemical/Antimetabolites, Antineoplastic,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Neoplasm,
http://linkedlifedata.com/resource/pubmed/chemical/Deoxyguanosine,
http://linkedlifedata.com/resource/pubmed/chemical/Methyltransferases,
http://linkedlifedata.com/resource/pubmed/chemical/Purine Nucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Purines,
http://linkedlifedata.com/resource/pubmed/chemical/Thioguanine,
http://linkedlifedata.com/resource/pubmed/chemical/Thionucleosides,
http://linkedlifedata.com/resource/pubmed/chemical/Thionucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/thiopurine methyltransferase
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| pubmed:status |
MEDLINE
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| pubmed:month |
Aug
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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 |
61
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
5810-6
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| pubmed:dateRevised |
2007-11-15
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| pubmed:meshHeading |
pubmed-meshheading:11479220-3T3 Cells,
pubmed-meshheading:11479220-6-Mercaptopurine,
pubmed-meshheading:11479220-Animals,
pubmed-meshheading:11479220-Antimetabolites, Antineoplastic,
pubmed-meshheading:11479220-Biotransformation,
pubmed-meshheading:11479220-Cytosol,
pubmed-meshheading:11479220-DNA, Neoplasm,
pubmed-meshheading:11479220-Deoxyguanosine,
pubmed-meshheading:11479220-Gene Transfer Techniques,
pubmed-meshheading:11479220-HeLa Cells,
pubmed-meshheading:11479220-Humans,
pubmed-meshheading:11479220-Leukemia-Lymphoma, Adult T-Cell,
pubmed-meshheading:11479220-Methyltransferases,
pubmed-meshheading:11479220-Mice,
pubmed-meshheading:11479220-Purine Nucleotides,
pubmed-meshheading:11479220-Purines,
pubmed-meshheading:11479220-Retroviridae,
pubmed-meshheading:11479220-Thioguanine,
pubmed-meshheading:11479220-Thionucleosides,
pubmed-meshheading:11479220-Thionucleotides,
pubmed-meshheading:11479220-Tumor Cells, Cultured
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| pubmed:year |
2001
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| pubmed:articleTitle |
Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells.
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| pubmed:affiliation |
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
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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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