Microbes mediate mining metals.

Levels of glutathione (GSH) in tumour tissue may be important in determining the clinical response to certain anticancer agents. Recent reports have suggested that D,L-buthionine-S,R-sulphoximine (BSO), a specific inhibitor of GSH synthesis, may be used to deplete tumour cell GSH and thus increase the therapeutic ratio of these agents. We have previously shown that 1-naphthol is a potential antitumour agent, and that its possible metabolite 1,4-naphthoquinone is thiol reactive and capable of redox cycling. It was therefore of interest to investigate the effect of pretreatment with BSO, on the toxicity of these agents, to tumour cells. For comparison we included three other cytotoxic agents, melphalan, helenalin and menadione, the toxicities of which are reported to be modulated by intracellular GSH. Depletion of GSH using BSO did not effect the toxicity of 1-naphthol, or 1,4-NQ but did produce slight potentiation of the cytotoxicities of menadione, helanalin and melphalan. The lack of effect of BSO on 1-naphthol and 1,4-NQ is not easily explained but if one also considers the modest potentiation of cytotoxicity achieved with the other agents studied, the potential use of BSO in combined chemotherapy is at best rather modest. Based on our findings that l-naphthol is selectively toxic to short term organ cultures of human colonic tumour tissue compared to normal colonic tissue from the same patients, we suggested the potential use of l-naphthol or related compounds in cancer chemotherapy (Cohen et al., 1983; Wilson et al., 1985). Recently we have also shown an antitumour activity of l-naphthol against Ehrlich ascites tumour cells (Jones et al., 1987) and it therefore is of interest to elucidate its mechanism of toxicity and formation of possible reactive metabolites. l-Naphthol may be metabolised by a microsomal mixed function oxidase to cytotoxic naphthoquinones, primarily 1,4-naphthoquinone (d'Arcy Doherty et al., 1984a, b, 1985). The toxicity of both 1-naphthol and its possible metabolites 1,2-naphthoquinone and 1,4-naphthoquinone, to isolated hepatocytes, is prececed by a rapid depletion of intracellular glutathione (GSH) (d'Arcy Doherty et al., 1984b). GSH is the major nonprotein thiol in the cell and plays a critical role in cellular defences against oxidative stress, free radicals and alkylating agents (Meister & Anderson, 1979). One of the problems associated with chemotherapy is the wide range of sensitivities to treatment with any or one agent, which is thought to be, in part, due to the differences in sulphydryl levels in tumours. Several recent reports, have therefore considered the …