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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
5
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pubmed:dateCreated |
1994-12-22
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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.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-1309432,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-1349338,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-1356076,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-1423616,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-1593647,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-1614522,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-1656362,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-1905840,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2046748,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2154857,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2155063,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2168281,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2170589,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2173600,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2187602,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2456901,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2537142,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2549204,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2549853,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2554494,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2660073,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2829215,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-2918334,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-3006754,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-3019531,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-3037573,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-3345800,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-3581418,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-4771975,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-6377075,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-6572554,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-8306412,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-8402885,
http://linkedlifedata.com/resource/pubmed/commentcorrection/7947097-8479523
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0007-0920
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
70
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pubmed:geneSymbol |
p53
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
914-21
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:7947097-Bromodeoxyuridine,
pubmed-meshheading:7947097-Carcinoma, Small Cell,
pubmed-meshheading:7947097-Cell Cycle,
pubmed-meshheading:7947097-DNA Damage,
pubmed-meshheading:7947097-DNA Topoisomerases, Type II,
pubmed-meshheading:7947097-Etoposide,
pubmed-meshheading:7947097-Flow Cytometry,
pubmed-meshheading:7947097-G1 Phase,
pubmed-meshheading:7947097-Genes, p53,
pubmed-meshheading:7947097-Humans,
pubmed-meshheading:7947097-Kinetics,
pubmed-meshheading:7947097-Lung Neoplasms,
pubmed-meshheading:7947097-Mutation,
pubmed-meshheading:7947097-S Phase,
pubmed-meshheading:7947097-Tumor Cells, Cultured
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pubmed:year |
1994
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pubmed:articleTitle |
Etoposide-induced cell cycle delay and arrest-dependent modulation of DNA topoisomerase II in small-cell lung cancer cells.
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pubmed:affiliation |
MRC Clinical Oncology and Radiotherapeutics Unit, MRC Centre, Cambridge, UK.
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pubmed:publicationType |
Journal Article
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