Augmentation of cisplatin (DDP) cytotoxicity in vivo by DL-buthionine sulfoximine (BSO) in DDP-sensitive and-resistant rat ovarian tumors and its relation to DNA interstrand cross links

Abstract

DDP treatment (1.2 mg/kg x 5) prolonged the mean survival time (MST) of rats bearing an experimental ovarian tumor (0-342) from 16.4 to 51.1 days, with one of ten rats surviving more than 90 days. Administration of D,L - buthionine sulfoximine (BSO) (24 and 2 h prior to DDP, respectively) before the last two doses of DDP had no significant effect on DDP therapeutic activity, while daily combination of DDP with BSO (BSO 2 h prior to DDP) throughout the treatment significantly increased MST to 69 days (p less than 0.05, vs. DDP alone), with three of ten rats surviving more than 90 days. In the DDP resistant counterpart (0-342/DDP), on the other hand, DDP alone showed only a slight increase of MST (11.6 days in DDP group vs. 10.7 days in control group), addition of BSO to DDP treatment further prolonged MST to 13.3 days (p less than 0.01 vs. DDP alone). The formation of DNA interstrand cross links (DNA-ISCL) was found to be higher in 0-342 than in 0-342/DDP cells in vitro with a maximum at 24 h following 1 h exposure to DDP. BSO depleted the intracellular GSH level in a dose - and time - dependent manner in the two cell lines. Pretreatment with BSO resulted in a 7.4% increase in DNA-ISCL by DDP in 0-342 cells but a 39% increase in 0-342/DDP cells, which may partially account for chemosensitization of BSO to DDP in vivo. Our result that the chemosensitizing effect of BSO, through depletion of cellular GSH, is more significant in the DDP sensitive O-342 tumor than in its DDP resistant subline in vivo underlines that BSO should be used as a chemosensitizer in combination with DDP at the beginning of chemotherapy for clinical trial.