Linked Life Data

20371715

Source:http://linkedlifedata.com/resource/pubmed/id/20371715

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2010-4-9
pubmed:abstractText
Trifluorothymidine (TFT) is part of the novel oral formulation TAS-102, which is currently evaluated in phase II studies. Drug resistance is an important limitation of cancer therapy. The aim of the present study was to induce resistance to TFT in H630 colon cancer cells using two different schedules and to analyze the resistance mechanism. Cells were exposed either continuously or intermittently to TFT, resulting in H630-cTFT and H630-4TFT, respectively. Cells were analyzed for cross-resistance, cell cycle, protein expression, and activity of thymidine phosphorylase (TP), thymidine kinase (TK), thymidylate synthase (TS), equilibrative nucleoside transporter (hENT), gene expression (microarray), and genomic alterations. Both cell lines were cross-resistant to 2'-deoxy-5-fluorouridine (>170-fold). Exposure to IC(75)-TFT increased the S/G(2)-M phase of H630 cells, whereas in the resistant variants, no change was observed. The two main target enzymes TS and TP remained unchanged in both TFT-resistant variants. In H630-4TFT cells, TK protein expression and activity were decreased, resulting in less activated TFT and was most likely the mechanism of TFT resistance. In H630-cTFT cells, hENT mRNA expression was decreased 2- to 3-fold, resulting in a 5- to 10-fold decreased TFT-nucleotide accumulation. Surprisingly, microarray-mRNA analysis revealed a strong increase of secretory phospholipase-A2 (sPLA2; 47-fold), which was also found by reverse transcription-PCR (RT-PCR; 211-fold). sPLA2 inhibition reversed TFT resistance partially. H630-cTFT had many chromosomal aberrations, but the exact role of sPLA2 in TFT resistance remains unclear. Altogether, resistance induction to TFT can lead to different mechanisms of resistance, including decreased TK protein expression and enzyme activity, decreased hENT expression, as well as (phospho)lipid metabolism. Mol Cancer Ther; 9(4); 1047-57. (c)2010 AACR.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1538-8514
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
9
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1047-57
pubmed:meshHeading
pubmed-meshheading:20371715-Cell Cycle, pubmed-meshheading:20371715-Cell Line, Tumor, pubmed-meshheading:20371715-Cell Proliferation, pubmed-meshheading:20371715-Comparative Genomic Hybridization, pubmed-meshheading:20371715-DNA Copy Number Variations, pubmed-meshheading:20371715-Down-Regulation, pubmed-meshheading:20371715-Drug Resistance, Neoplasm, pubmed-meshheading:20371715-Enzyme Inhibitors, pubmed-meshheading:20371715-Equilibrative Nucleoside Transport Proteins, pubmed-meshheading:20371715-Gene Expression Profiling, pubmed-meshheading:20371715-Gene Expression Regulation, Neoplastic, pubmed-meshheading:20371715-Humans, pubmed-meshheading:20371715-Lipid Metabolism, pubmed-meshheading:20371715-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:20371715-Phospholipases A2, Secretory, pubmed-meshheading:20371715-Thymidine Kinase, pubmed-meshheading:20371715-Thymidylate Synthase, pubmed-meshheading:20371715-Trifluridine, pubmed-meshheading:20371715-Up-Regulation
pubmed:year
2010
pubmed:articleTitle
Trifluorothymidine resistance is associated with decreased thymidine kinase and equilibrative nucleoside transporter expression or increased secretory phospholipase A2.
pubmed:affiliation
Department of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, the Netherlands.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't