Low-dose cisplatin and 5-fluorouracil in combination can repress increasedgene expression of cellular resistance determinants to themselves

dThe synergistic mechanism of cisplatin (CDDP) and 5-fluorouracil (5-FU) in combination remains unclear, despite its substantial antitumor activity, w hich has been demonstrated clinically. To clarify the mechanism(s), we dete r mined the sensitivity or resistance factors to either drug in seven gastr ointestinal cancer cell lines and then analyzed the altered gene expression after different exposures to CDDP and 5-FU. At the basal gene expression l evel, glutathione S-transferase pi (GST pi) expression correlated with the observed resistance to CDDP, whereas dihydropyrimidine dehydrogenase (DPD) and multidrug resistance-associated protein (MRP) expression was related to 5-FU resistance. GST pi, DPD, and MRP expression increased in response to the respective drug, but they also increased in response to the other drug as well. Additionally, 5-FU revealed a drastically increased thymidylate sy nthase (TS) gene expression in 5-FU-resistant cells. However, the increasin g actions of CDDP and 5-FU on GST pi, DPD, MRP, and TS expression varied ac cording to the exposure time, concentration, and schedule, A low concentrat ion of CDDP (1 mu g/ml, 30 min) follow ed by 5-FU (0.5 mu g/ml, 72 h) was f ound to cause a less increased expression of DPD, MRP, GST pi, and TS than either drug alone, thus resulting in synergistic cytotoxicity in 5-FU-resis tant COLO201 and CDDP-resistant HCC-48 cells. The sequential combination of CDDP and 5-FU inhibited the growth of human normal renal proximal tubule c ells by less than 20%. Low concentrations of CDDP followed by continuous ex posure to 5-FU can repress increased gene expression related to both drug r esistances, thereby being synergistically cytotoxic in human gastrointestin al cancer cells.