Abstract
Two and four treatments of 5 mmol kg-1 of buthionine sulfoximine (BSO) at an interval of 12 h depleted the glutathione (GSH) content in NFSa tumours of C3H/He mice, respectively, to 24.0 and 1.78 percent of the untreated controls. BSO pre-treatments every 12 h enhanced the cytotoxicity of cyclophosphamide (CYC) towards artificial lung micrometastases of NFSa tumours giving enhancement ratios (ERs) ranging from 1.75 to 1.83 and from 2.41 to 2.73, for two and four BSO pretreatments respectively. Large ERs were obtained at low CYC doses (high cell survival). Four BSO pre-treatments at an interval of 12 h did not increase the cytotoxicity of CYC to bone marrow stem cells. Our results suggest a clinical applicability of the combination of BSO and CYC.
Highlights
Cellular sulfhydryls, especially glutathione (GSH), have been found to protect cells via detoxification of alkylating agents such as nitrogen mustard (Arrick & Nathan, 1984)
Two buthionine sulfoximine (BSO) treatments given at 12h intervals reduced the non-protein sulfhydryl (NPSH), GSH and cysteine contents of tumours to 36.9, 24.0 and
The response of lung micrometastases which were treated with CYC 12 h after tumour cell injection was described by an exponential survival curve with a small shoulder (Figure 2)
Summary
Especially glutathione (GSH), have been found to protect cells via detoxification of alkylating agents such as nitrogen mustard (Arrick & Nathan, 1984). The relationship between the sensitivity of tumour cells to nitrogen mustard and their sulfhydryl contents has been demonstrated by several investigators (Hirono, 1961; Calcutt & Connors, 1963; Ball et al, 1966; Goldberg, 1969; Morita, 1973; Begleiter et al, 1983). The increased sensitivity of cells to melphalan following either the incubation of cells in cysteine-deficient medium or exposure to a non-protein sulfhydryl (NPSH) depleting agent, such as diethyl maleate (DEM) or buthionie sulfoximine (BSO), has been reported by several groups (Suzukake et al, 1982; Taylor et al, 1982; Green et al, 1984)
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