SEVERE DEPLETION OF CELLULAR THIOLS AND GLUTATHIONE-RELATED ENZYMES OF A CARMUSTINE-RESISTANT L1210 STRAIN ASSOCIATES WITH COLLATERAL SENSITIVITY TO CYCLOPHOSPHAMIDE

Cyclophosphamide (CPA) increased the life span of both carmustine (BCN U)-resistant (L1210/BCNU) and BCNU-sensitive L1210 (L1210/0) leukaemic mice; their sensitivity to CPA, however, was extremely different. The BCNU-resistant strain was much more sensitive (collaterally) to CPA t han was its sensitive counterpart. The collateral sensitivity was acco mpanied by a severe reduction in the activity of glutathione-related e nzymes and in protein thiol (SH) and non-protein SH levels in BCNU-res istant cells. The activity of glutathione reductase (GSSG-R) was 2 tim es higher in the L1210/0 cells than in the L1210/BCNU cells. Glutathio ne-S-transferase (GST) was also almost 2 times more active in the sens itive cells than in the resistant strain. To develop resistance agains t CPA with a single treatment (60 mg/kg) per passage, the L1210/BCNU s train needed 26 passages, whereas the L1210/0 strain required signific antly fewer. The resistance developed against CPA was associated with a moderate elevation of thiols in the L1210/CPA cells, whereas this el evation was approximately 3 times more pronounced in the L1210/BCNU/CP A cells. The severely reduced activity of GST in the L1210/BCNU strain was markedly increased when these cells were made resistant to CPA; t he GSSG-R activity, however, remained low, suggesting an irreversible injury of this enzyme by BCNU.