| pubmed-article:7947097 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:7947097 | lifeskim:mentions | umls-concept:C0684249 | lld:lifeskim |
| pubmed-article:7947097 | lifeskim:mentions | umls-concept:C0334227 | lld:lifeskim |
| pubmed-article:7947097 | lifeskim:mentions | umls-concept:C0007586 | lld:lifeskim |
| pubmed-article:7947097 | lifeskim:mentions | umls-concept:C0012863 | lld:lifeskim |
| pubmed-article:7947097 | lifeskim:mentions | umls-concept:C1709059 | lld:lifeskim |
| pubmed-article:7947097 | lifeskim:mentions | umls-concept:C0205421 | lld:lifeskim |
| pubmed-article:7947097 | pubmed:issue | 5 | lld:pubmed |
| pubmed-article:7947097 | pubmed:dateCreated | 1994-12-22 | lld:pubmed |
| pubmed-article:7947097 | pubmed:abstractText | As an approach to the rational design of combination chemotherapy involving the anti-cancer DNA topoisomerase II poison etoposide (VP-16), we have studied the dynamic changes occurring in small-cell lung cancer (SCLC) cell populations during protracted VP-16 exposure. Cytometric methods were used to analyse changes in target enzyme availability and cell cycle progression in a SCLC cell line, mutant for the tumour-suppressor gene p53 and defective in the ability to arrest at the G1/S phase boundary. At concentrations up to 0.25 microM VP-16, cells became arrested in G2 by 24 h exposure, whereas at concentrations 0.25-2 microM G2 arrest was preceded by a dose-dependent early S-phase delay, confirmed by bromodeoxyuridine incorporation. Recovery potential was determined by stathmokinetic analysis and was studied further in aphidicolin-synchronised cultures released from G1/S and subsequently exposed to VP-16 in early S-phase. Cells not experiencing a VP-16-induced S-phase delay entered G2 delay dependent upon the continued presence of VP-16. These cells could progress to mitosis during a 6-24 h period after drug removal. Cells experiencing an early S-phase delay remained in long-term G2 arrest with greatly reducing ability to enter mitosis up to 24 h after removal of VP-16. Irreversible G2 arrest was delimited by the induction of significant levels of DNA cleavage or fragmentation, not associated with overt apoptosis, in the majority of cells. Western blotting of whole-cell preparations showed increases in topoisomerase II levels (up to 4-fold) attributable to cell cycle redistribution, while nuclei from cells recovering from S-phase delay showed enhanced immunoreactivity with an anti-topoisomerase II alpha antibody. The results imply that traverse of G1/S and early S-phase in the presence of a specific topoisomerase II poison gives rise to progressive low-level trapping of topoisomerase II alpha, enhanced topoisomerase II alpha availability and the subsequent irreversible arrest in G2 of cells showing limited DNA fragmentation. We suggest that protracted, low-dose chemotherapeutic regimens incorporating VP-16 are preferentially active towards cells attempting G1/S transition and have the potential for increasing the subsequent action of other topoisomerase II-targeted agents through target enzyme modulation. Combination modalities which prevent such dynamic changes occurring would act to reduce the effectiveness of the VP-16 component. | lld:pubmed |
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| pubmed-article:7947097 | pubmed:language | eng | lld:pubmed |
| pubmed-article:7947097 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:7947097 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:7947097 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
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| pubmed-article:7947097 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:7947097 | pubmed:month | Nov | lld:pubmed |
| pubmed-article:7947097 | pubmed:issn | 0007-0920 | lld:pubmed |
| pubmed-article:7947097 | pubmed:author | pubmed-author:BleehenN MNM | lld:pubmed |
| pubmed-article:7947097 | pubmed:author | pubmed-author:SmithP JPJ | lld:pubmed |
| pubmed-article:7947097 | pubmed:author | pubmed-author:WatsonJ VJV | lld:pubmed |
| pubmed-article:7947097 | pubmed:author | pubmed-author:FineJ SJS | lld:pubmed |
| pubmed-article:7947097 | pubmed:author | pubmed-author:GottliebTT | lld:pubmed |
| pubmed-article:7947097 | pubmed:author | pubmed-author:OsborneR JRJ | lld:pubmed |
| pubmed-article:7947097 | pubmed:author | pubmed-author:SouèsSS | lld:pubmed |
| pubmed-article:7947097 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:7947097 | pubmed:volume | 70 | lld:pubmed |
| pubmed-article:7947097 | pubmed:geneSymbol | p53 | lld:pubmed |
| pubmed-article:7947097 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:7947097 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:7947097 | pubmed:pagination | 914-21 | lld:pubmed |
| pubmed-article:7947097 | pubmed:dateRevised | 2009-11-18 | lld:pubmed |
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| pubmed-article:7947097 | pubmed:year | 1994 | lld:pubmed |
| pubmed-article:7947097 | pubmed:articleTitle | Etoposide-induced cell cycle delay and arrest-dependent modulation of DNA topoisomerase II in small-cell lung cancer cells. | lld:pubmed |
| pubmed-article:7947097 | pubmed:affiliation | MRC Clinical Oncology and Radiotherapeutics Unit, MRC Centre, Cambridge, UK. | lld:pubmed |
| pubmed-article:7947097 | pubmed:publicationType | Journal Article | lld:pubmed |
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