Schedule-dependent reversion of cisplatin resistance by 5-fluorouracil in a cisplatin-resistant human lung adenocarcinoma cell line A(549)(DDP)

Objective To study the schedule-dependent reversion of cis-diamminedichloro platinum (CDDP) resistance by 5-fluorouracil (5-Fu) in a CDDP resistant hum an lung adenocarcinoma cell line A(549)(DDP). Methods Dimethylthiazol dipheryltetrazolium bromide (MTT) assay and immunoc ytochemistry were used. Results After the A(549)(DDP) was treated with CDDP, followed immediately b y exposure to 5-Fu, cytotoxicity of CDDP increased 1.8 fold. After pretreat ment of A(549)(DDP) with 5-Fu, followed immediately by exposure to CDDP, th e cytotoxicity of CDDP increased 3.9 fold. After pretreatment of A(549)(DDP ) with 5-Fu, after a 24- or 48-hour drug-free interval, followed by exposur e to CDDP, the cytotoxicity of CDDP increased 20 and 250 fold, respectively , and the A(549)(DDP) was rendered more sensitive than its parental cell li ne A(549). In parallel with the increased cytotoxicity, the cellular GSH co ntent was significantly reduced at 24 or 48-hour after 5-Fu pretreatment. H owever, depletion of GSH by buthionine sulfoximine (BSO) only resulted in p artial reversion of CDDP resistance. 5-Fu could also inhibit the expression of MRP, but had no effect on the expression of GST pi. The effect of 5-Fu on the parental cell line A(549) was much smaller than that in A(549)(DDP). Conclusion Scheduled administration of 5-Fu can reverse CDDP resistance com pletely through reduction of GSH and inhibition of MRP expression.