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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
3
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pubmed:dateCreated |
1989-10-16
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pubmed:abstractText |
Primary resistance to chemotherapeutic agents is a major problem in the management of advanced cancer. By using oestrogen to modulate the topoisomerase II content of T-47D human breast cancer cells, we show here that cell subpopulations resistant to the topoisomerase-II-interactive drug VPI6 (etoposide) can be identified and quantified using single-cell analytical techniques. Immunohistochemical studies reveal topoisomerase II to be present in approximately 10% of control cells compared with 30% of oestrogen-stimulated cells, and this difference is reflected in the proportions of cells exhibiting VPI6-induced cell-cycle delay. This moderate increase in overall cell sensitivity is accompanied by massive enhancement of clonogenic cell kill, suggesting that oestrogen enhances VPI6 cytotoxicity by recruiting a clonogenic cell subpopulation characterized by increased topoisomerase II content. Flow cytometry confirms that the increase in topoisomerase II is localized to an activated G1-phase cell subset. We conclude that (i) single-cell analysis of cellular topoisomerase II content is predictive of VPI6 chemosensitivity; (ii) the existence of resistant tumour-cell subpopulations does not necessarily indicate the presence of phenotypically divergent subclones; and (iii) rational strategies for eliminating tumour resistance may be based on biological manipulation of specific cytotoxic drug targets.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
Sep
|
pubmed:issn |
0020-7136
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
15
|
pubmed:volume |
44
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pubmed:owner |
NLM
|
pubmed:authorsComplete |
Y
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pubmed:pagination |
501-5
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:2550374-Breast Neoplasms,
pubmed-meshheading:2550374-Cell Cycle,
pubmed-meshheading:2550374-DNA Topoisomerases, Type II,
pubmed-meshheading:2550374-Drug Resistance,
pubmed-meshheading:2550374-Estrogens,
pubmed-meshheading:2550374-Etoposide,
pubmed-meshheading:2550374-Female,
pubmed-meshheading:2550374-Flow Cytometry,
pubmed-meshheading:2550374-Humans,
pubmed-meshheading:2550374-Immunohistochemistry,
pubmed-meshheading:2550374-Neoplastic Stem Cells,
pubmed-meshheading:2550374-Tumor Cells, Cultured
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pubmed:year |
1989
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pubmed:articleTitle |
Oestrogen potentiates topoisomerase-II-mediated cytotoxicity in an activated subpopulation of human breast cancer cells: implications for cytotoxic drug resistance in solid tumours.
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pubmed:affiliation |
MRC Unit, Cambridge.
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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