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Low-Dose Cisplatin and 5-Fluorouracil in Combination CanRepress Increased Gene Expression of Cellular Resistance Determinants to Themselves¹

Department of Biochemistry and Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553 [M. N., W. Y., J-S. P., R. O., H. H., H. T.]; The First Department of Surgery, Chiba University School of Medicine, Chiba 260-8670 [N. S.]; Laboratory of Pathogenic Biochemistry in Medicine, Taiho Pharmaceutical Co., Ltd., Tokyo 101-0054 [T. S.]; and Department of Internal Medicine, Showa University Toyosu Hospital, Tokyo 142-8577 [M. M., M. K.], Japan

The synergistic mechanism of cisplatin (CDDP) and 5-fluorouracil (5-FU) in combination remains unclear, despite its substantial antitumor activity, which has been demonstrated clinically. To clarify the mechanism(s), we determined the sensitivity or resistance factors to either drug in seven gastrointestinal cancer cell lines and then analyzed the altered gene expression after different exposures to CDDP and 5-FU. At the basal gene expression level, glutathione S-transferase (GST) 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, 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 synthase (TS) gene expression in 5-FU-resistant cells. However, the increasing actions of CDDP and 5-FU on GST, DPD, MRP, and TS expression varied according to the exposure time, concentration, and schedule. A low concentration of CDDP (1 µg/ml, 30 min) followed by 5-FU (0.5 µg/ml, 72 h) was found to cause a less increased expression of DPD, MRP, GST, and TS than either drug alone, thus resulting in synergistic cytotoxicity in 5-FU-resistant COLO201 and CDDP-resistant HCC-48 cells. The sequential combination of CDDP and 5-FU inhibited the growth of human normal renal proximal tubule cells by less than 20%. Low concentrations of CDDP followed by continuous exposure to 5-FU can repress increased gene expression related to both drug resistances, thereby being synergistically cytotoxic in human gastrointestinal cancer cells.

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