Potentiation of nitrogen mustard cytotoxicity by disulfiram, diethyldithiocarbamic acid, and diethylamine in mice

Abstract

Disulfiram (DSF) and its metabolites, diethyldithiocarbamic acid (DDC) and diethylamine (DEA), were studied as pretreatments in combination with the alkylating agent nitrogen mustard (HN2) on the cytotoxicity of HN2 against both leukemia cells and normal hematopoietic stem cells. Both time intervals and dose relationships were examined. DSF showed a substantial potentiation of HN2 cytotoxicity against murine AKR leukemia cell spleen colony-forming units (LCFU) when given i.p. between 15 to 30 min prior to HN2 i.v. treatment. For 3 mg DSF/mouse pretreatment, leukemia LCFU survival was about 10(-6) whereas it was about 10(-2) for HN2 alone. The extent of this potentiation decreased as the time between treatments increased. Significant potentiation was noted even when a low dose of DSF (0.25 mg/mouse) was administered 15 min before HN2. However, DSF had little if any effect on the modulation of HN2 cytotoxicity to normal hematopoietic cell spleen colony-forming units (NCFU). DDC showed an increasing potentiation of HN2 cytotoxicity against LCFU when given i.p. prior to HN2 i.v. treatment. The maximum effect was noted between 2 and 4 h with a surviving fraction for LCFU between 10(-5) and 10(-6) for 20 mg/mouse DDC pretreatment. The extent of this effect then decreased as the time interval increased beyond 4 h, but it was still significant for the 24-h interval. This pronounced potentiation effect was dose dependent for DDC. The compound exhibited a protective effect against HN2 cytotoxicity to NCFU when given 15 min before HN2. This protection decreased with increased time interval. DEA (20 mg/mouse) did not show a significant potentiation of HN2 cytotoxicity against LCFU when administered i.p. prior to HN2. Also, DEA did not show any significant protection of NCFU.