THE INTERACTION OF BUTHIONINE SULPHOXIMIDE (BSO) AND THE TOPOISOMERASE-I INHIBITOR CPT-11

Buthionine sulphoximide (BSO)-induced depletion of glutathione (GSH) w as found to be associated with an increased sensitivity to CPT-11 (top oisomerase I-reactive agent) in V79 hamster lung fibroblast cells. Whe n V79 cells were exposed to 2.5 mM BSO for 28 h beginning 4 h prior to a 24 h coincubation with CPT-11, cytotoxicity was increased compared with CPT-11 alone. It was determined that BSO resulted in a GI cell cy cle arrest and a decrease in the percentage of cells in S-phase. Since CPT-11 is known to be S-phase-specific, this BSO-induced cell cycle r edistribution did not appear to account for the chemosensitisation of CPT-11. Additionally, BSO did not alter intracellular accumulation of CPT-11. conversion of CPT-11 to its active metabolite SN-38, or efflux of either CPT-11 or SN-38 from the cell. Finally, BSO resulted in a s light reduction, rather than an increase, in the number of stabilised DNA-topoisomerase I complexes induced by CPT-11. Therefore, these resu lts suggest that BSO-induced sensitisation of V79 cells to the cytotox ic effects of CPT-11 occurs by a mechanism independent of the stabilis ation of DNA-topoisomerase I complexes.