Document Detail

The schedule-dependent effects of etoposide in leukaemic cell lines: a function of concentration and duration.
MedLine Citation:
PMID:  12721756     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Etoposide is a commonly used anticancer agent that is highly schedule-dependent. The in vitro activity of etoposide (0-10 microM) was investigated in a panel of leukaemic cell lines. METHODS: Cells were cultured with etoposide in drug schedules of equal exposure duration (ED, durationxconcentration), and the effects of drug exposure on cell parameters, including cell cycle distribution, were assessed over an 8-day period. RESULTS: Proliferation assays indicated a concentration- and duration-dependent induction of cell death by etoposide in CEM and HL60 cells, and flow cytometric analysis indicated that this cell kill was by apoptosis. Efficacy was also dependent upon schedule, with more cell kill seen in schedules of longer duration. As an example, accumulative percent cell kill resulting from a continuous exposure to 0.05 microM etoposide was significantly greater than that in cultures involving either a 4-day exposure to 0.1 microM or a single-day exposure to 0.4 microM etoposide (193.4+/-15.9% vs 125.2+/-5.4% vs 42.3+/-5.9%, respectively; P<0.001 in all cases; equi-ED 0.4 microM.days). Efficacy was also dependent upon the ED of the schedule. At very low concentrations, the initial enhancement of cytotoxicity mediated by increasing duration would gradually and paradoxically be lost in the more protracted schedules (e.g. accumulative percent cell kill 66.4+/-7.4%, 158.3+/-12.0% and 40.1+/-6.0% with 100 n M for 2 days, 33 n M for 6 days and 25 n M for 8 days, respectively; P<0.001 in all cases; equi-ED 0.2 microM x days). CONCLUSIONS: Our results confirm the schedule-dependency of etoposide in vitro, highlighting the importance of total duration of drug exposure in determining cytotoxicity, and emphasizing the requirement to achieve a cytotoxic concentration in longer exposures. It is therefore crucial to ensure that etoposide regimens used clinically involve doses that are effectively cytotoxic.
Wai M Liu; Simon P Joel
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Publication Detail:
Type:  Journal Article     Date:  2003-03-05
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  51     ISSN:  0344-5704     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  2003 Apr 
Date Detail:
Created Date:  2003-04-30     Completed Date:  2003-06-27     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  291-6     Citation Subset:  IM    
New Drug Study Group, Department of Medical Oncology, St. Bartholomew's Hospital, 38 Little Britain, West Smithfield, London, EC1A 7BE, UK.
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MeSH Terms
Antineoplastic Agents, Phytogenic / administration & dosage,  pharmacology*
Cell Cycle / drug effects*
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Administration Schedule
Etoposide / administration & dosage,  pharmacology*
Leukemia / pathology*
Time Factors
Tumor Cells, Cultured
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 33419-42-0/Etoposide

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