The upregulation of dihydropyrimidine dehydrogenase in liver is involved in acquired resistance to 5-fluorouracil

Background: Acquired resistance to 5-fluorouracil (5-FU) is one of the important reasons for failure in 5-FU-based chemotherapy. The upregulation of dihydropyrimidine dehydrogenase (DPD) in tumours was reported as an important factor for acquired 5-FU resistance. The aim of this study is to examine whether intra-hepatic DPD was involved in acquired 5-FU resistance. Methods: HT-29 human colorectal xenograft tumours were established in nude mice. After long-term exposure to 5-FU, some of the tumour became resistant and the others remained sensitive to 5-FU. DPD expression levels in the livers and tumours of resistant, sensitive or untreated mice were examined, and pharmacokinetics of 5-FU in rats' plasma were investigated. Gimeracil, a DPD inhibitor, was checked whether it could reverse the reduced bioavailability of 5-FU. Results: DPD expression was upregulated obviously in tumours of resistant mice as reported previously. Importantly, DPD expression was also upregulated significantly in livers of resistant mice, compared with those of sensitive or untreated mice. Furthermore, the upregulation of DPD expression in livers led to accelerated metabolism of 5-FU. Gimeracil was found to reverse the reduced serum 5-FU concentration. The cultured tumour cells from 5-FU treated mice showed relative sensitivity to higher concentration of 5-FU, even the resistant tumour cells. Conclusion: Our study suggested that the upregulation of DPD in liver may be involved in acquired resistance to 5-FU, and DPD inhibitors or increasing 5-FU dosage may have potential application in overcoming 5-FU acquired resistance. (C) 2012 Elsevier Ltd. All rights reserved.