Document Detail


Differential sensitivity to etoposide (VP-16)-induced S phase delay in a panel of small-cell lung carcinoma cell lines with G1/S phase checkpoint dysfunction.
MedLine Citation:
PMID:  11269739     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: The highly schedule-dependent cytotoxic agent etoposide (VP-16) is initially effective in the treatment of small-cell lung cancer (SCLC), particularly in multidrug combination chemotherapy. Heterogeneity in cellular sensitivity to cell cycle arrest may underpin the inadequacy of low-dose extended-cycle single-agent regimes in tumours with partially dysfunctional apoptotic signalling pathways. We have studied the longevity and dose dependency of cell cycle and to a limited extent the apoptotic responses of a panel of seven unselected SCLC cell lines, screened for TP53 status. METHODS: Cells were analysed using flow cytometry for the cell cycle responses and field inversion gel electrophoresis for apoptotic patterns. The mitotic inhibitor nocodazole was used to assess and correct cell line response data for differences in cell cycle traverse per se. RESULTS: An overall lack of G1/S arrest and muted DNA fragmentation were consistent with the presence of TP53 gene abnormalities. Maximal G2 arrest but with clear recovery potential occurred at an exposure dose (ED, concentration of drug x time) value of approximately 24 microM h. Higher doses (ED values >48 microM h) revealed a wide variation in S phase delay that was independent of population doubling time and could not be compensated for by drug concentration changes alone. CONCLUSION: The results suggest that heterogeneity in the in vitro sensitivity of unselected SCLC cell lines to S phase arrest is demonstrable at ED values projected to be critical for clinical activity. Such variation in S phase responsiveness may reflect differences in checkpoint activation and offer a functional target for the design of more-effective combination therapy.
Authors:
S Soués; M Wiltshire; P J Smith
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  47     ISSN:  0344-5704     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  2001  
Date Detail:
Created Date:  2001-03-27     Completed Date:  2001-04-05     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  133-40     Citation Subset:  IM    
Affiliation:
Laboratoire de Biologie Cellulaire, UFR Biomédicale des Saints Pères, Université René Descartes--Paris V, France.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Phytogenic / pharmacology*
Carcinoma, Small Cell / drug therapy*,  pathology
DNA Fragmentation / drug effects
Etoposide / pharmacokinetics,  pharmacology*
G1 Phase
Genes, p53
Humans
Lung Neoplasms / drug therapy*,  pathology
S Phase / drug effects*
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 33419-42-0/Etoposide

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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