Drug-induced death of leukaemic cells after G2/M arrest: higher order DNA fragmentation as an indicator of mechanism

Many reports have documented apoptotic death in different cell types within hours of exposure to cytotoxic drugs; lower drug concentrations may cause cell cycle arrest at G2/M and subsequent death, which has been distinguished from 'classic' apoptosis. We have analysed etoposide-induced ce...

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Bibliographic Details
Published in:British journal of cancer 1998-01, Vol.77 (1), p.40-50
Main Authors: Sleiman, RJ, Catchpoole, DR, Stewart, BW
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents, Phytogenic - pharmacology
Apoptosis - drug effects
Biological and medical sciences
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cell Division - drug effects
Cell Size - drug effects
Chemotherapy
Coloring Agents
DNA Fragmentation
DNA, Neoplasm
Drug Resistance
Electrophoresis, Gel, Pulsed-Field
Epidemiology
Etoposide - pharmacology
experimental-oncology
G2 Phase - drug effects
Gene Expression - drug effects
Humans
Leukemia - genetics
Leukemia - pathology
Medical sciences
Mitosis - drug effects
Molecular Medicine
Oncology
Pharmacology. Drug treatments
Polymerase Chain Reaction
Trypan Blue
Tumor Cells, Cultured - drug effects
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Summary:Many reports have documented apoptotic death in different cell types within hours of exposure to cytotoxic drugs; lower drug concentrations may cause cell cycle arrest at G2/M and subsequent death, which has been distinguished from 'classic' apoptosis. We have analysed etoposide-induced cell death in two lymphoblastoid T-cell lines, CCRF-CEM and MOLT-4, specifically in relation to DNA cleavage as indicated by pulse-field gel and conventional electrophoresis. High (5 microM) concentration etoposide causes 50-kb cleavage of DNA that occurs at the same time as apoptotic morphology and internucleosomal cleavage. At lower concentrations (0.5-0.05 microM), sequential change may be discerned with altered gene expression being similar to that at high dose, but preceding cell cycle arrest and 50-kb cleavage. These last changes, in turn, clearly precede internucleosomal fragmentation of DNA, vital dye staining and morphological evidence cell death. The pattern of higher order fragmentation constitutes a sensitive indicator of commitment to cell death in these cells. Morphological evidence of cell death is associated with internucleosomal fragmentation in one of the lines, but the pattern of 50-kb DNA cleavage provides the clearest evidence of commonality in death processes occurring at low and high drug concentration.
ISSN:0007-0920
1532-1827
DOI:10.1038/bjc.1998.7