Schedule-dependent reversion of cisplatin resistance by 5-fluorouracil in a cisplatin-resistant human lung adenocarcinoma cell line A549DDP.

OBJECTIVE

To study the schedule-dependent reversion of cis-diamminedichloroplatinum (CDDP) resistance by 5-fluorouracil (5-Fu) in a CDDP resistant human lung adenocarcinoma cell line A549DDP.

METHODS

Dimethylthiazol dipheryltetrazolium bromide (MTT) assay and immunocytochemistry were used.

RESULTS

After the A549DDP was treated with CDDP, followed immediately by exposure to 5-Fu, cytotoxicity of CDDP increased 1.8 fold. After pretreatment of A549DDP with 5-Fu, followed immediately by exposure to CDDP, the cytotoxicity of CDDP increased 3.9 fold. After pretreatment of A549DDP with 5-Fu, after a 24- or 48-hour drug-free interval, followed by exposure to CDDP, the cytotoxicity of CDDP increased 20 and 250 fold, respectively, and the A549DDP was rendered more sensitive than its parental cell line A549. In parallel with the increased cytotoxicity, the cellular GSH content was significantly reduced at 24 or 48-hour after 5-Fu pretreatment. However, depletion of GSH by buthionine sulfoximine (BSO) only resulted in partial 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 A549 was much smaller than that in A549DDP.

CONCLUSION

Scheduled administration of 5-Fu can reverse CDDP resistance completely through reduction of GSH and inhibition of MRP expression.