Abstract
Hypoxic cell radiosensitisers (e.g., misonidazole) have entered clinical trials in a number of countries throughout the world (e.g., UK, USA, Canada, South Africa and Japan). Although a slight benefit has been observed in some tumour sites, it is generally agreed that the dose of misonidazole (MISO) that can be given to patients is too low to allow for maximal sensitisation of hypoxic tumour cells (Dische, 1980). Endeavours to overcome the neurotoxic properties of MISO have led to the development of drugs that are less lipophilic (Brown & Lee, 1980) or that are more rapidly excreted from the body (Workman, 1980). An alternative approach has been to search for agents that will enhance the efficacy of existing radiosensitisers, hopefully without increasing their toxic side effects. One approach involves depleting intracellular glutathione (GSH), the major intracellular free thiol; for example, by binding GSH with diethyl maleate (DEM) (Bump et al, 1982) or by blocking GSH synthesis with buthiunine sulphoximine (BSO) (Griffith & Meister, 1979). These approaches are based upon the rationale that intracellular thiols compete with radiosensitisers (i.e., MISO or oxygen) for repair or fixation of radiation-induced damage (Alexander & Charlesby, 1955).
Published Version
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