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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, METHODS, RESULTS. Meshes: Animals, Antimetabolites, Antineoplastic, Blotting, Western, Cell Proliferation, Colorectal Neoplasms, Dihydrouracil Dehydrogenase (NADP), Drug Resistance, Neoplasm, Female, Fluorouracil, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, HT29 Cells, Humans, Liver, Mice, Mice, Inbred BALB C, Mice, Nude, Pyridines, Rats, Reverse Transcriptase Polymerase Chain Reaction, Tumor Burden, Up-Regulation, Xenograft Model Antitumor Assays.
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Is the upregulation of dihydropyrimidine dehydrogenase in liver involved in acquired resistance to 5-fluorouracil? Context: 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. 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. 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.
assistant
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. Final Decision: yes