Effects of the lipophilic anticancer drug teniposide (VM-26) on membrane transport

Wright, Stephen E.; Hines, Leigh H.; White, Jay D.

doi:10.1016/0009-2797(90)90020-n

Cited by 5 publications

(1 citation statement)

References 26 publications

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“…The peak plasma concentration of etoposide in standard therapeutic protocols is 25–75μM and recedes within 6h (Chabner et al., 2005; Relling et al., 1998). Although lipophilic, in tissue culture the intracellular concentration of etoposide equilibrates with the extracellular concentration (Wright et al., 1990). Thus treatment of tissue culture cells with 25μM etoposide provides an approximate mimic of peak in vivo exposure and is a concentration at which physiologically relevant cellular responses may be expected to be acutely activated, with subsequent washout of the medium allowing for rapid depletion of the drug from the cells.…”

Section: Resultsmentioning

confidence: 99%

Topoisomerase IIα‐dependent induction of a persistent DNA damage response in response to transient etoposide exposure

2009

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Cytotoxicity of the topoisomerase II (topoII) poison etoposide has been ascribed to the persistent covalent trapping of topoII in DNA cleavage complexes that become lethal as cells replicate their DNA. However, short term etoposide treatment also leads to subsequent cell death, suggesting that the lesions that lead to cytotoxicity arise rapidly and prior to the onset DNA replication. In the present study 1h treatment with 25muM etoposide was highly toxic and initiated a double-stranded DNA damage response as reflected by the recruitment of ATM, MDC1 and DNA-PKcs to gammaH2AX foci. While most DNA breaks were rapidly repaired upon withdrawal of the etoposide treatment, the repair machinery remained engaged in foci for at least 24h following withdrawal. TopoII siRNA ablation showed the etoposide toxicity and gammaH2AX response to correlate with the inability of the cell to correct topoIIalpha-initiated DNA damage. gammaH2AX induction was resistant to the inhibition of DNA replication and transcription, but was increased by pre-treatment with the histone deacetylase inhibitor trichostatin A. These results link the lethality of etoposide to the generation of persistent topoIIalpha-dependent DNA defects within topologically open chromatin domains.

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Section: Resultsmentioning

confidence: 99%