The effect of lowering intracellular glutathione (GSH) concentrations on the toxicity
of alkylating agents, and RNA synthesis inhibitor and topoisomerase 1 and 2 inhibitors
to a number of human leukaemic cell lines were evaluated. By using the GSH synthesis
inhibitor DL-buthionine-(S,R)-sulfoximine (BSO), GSH levels were artificially reduced.
Cells with low GSH concentrations were exposed to a number of cytotoxic agents and
the resultant mode of cell death was analysed using morphological and biochemical
criteria. It was found that untreated cells exposed to the above drugs underwent apoptosis
to varying extents. However, the toxicity of alkylating agents was dramatically increased
to all cell lines on lowering GSH levels, with the mode of cell death switching from
apoptosis to necrosis. The reduction of GSH levels had no effect on the toxicity of
actinomycin-D, camptothecin or etoposide, nor did it affect the mode of cell death
induced by these agents. These observations suggest that modulation of GSH levels
effect the toxicity of alkylating agents and that GSH influences the mode of cell
death induced by alkylating agents.