title: The upregulation of dihydropyrimidine dehydrogenase in liver is involved in acquired resistance to 5-fluorouracil.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Medical Oncology, Cancer Center, The State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 37, Guo Xue Xiang, Chengdu 610041, Sichuan Province, China.
authors: Long-Hao
authors: LH
authors: Li
authors: Hang
authors: H
authors: Dong
authors: Feng
authors: F
authors: Zhao
authors: Jie
authors: J
authors: Tang
authors: Xin
authors: X
authors: Chen
authors: Jing
authors: J
authors: Ding
authors: Hai-Tao
authors: HT
authors: Men
authors: Wu-Xia
authors: WX
authors: Luo
authors: Yang
authors: Y
authors: Du
authors: Jun
authors: J
authors: Ge
authors: Ben-Xu
authors: BX
authors: Tan
authors: Dan
authors: D
authors: Cao
authors: Ji-Yan
authors: JY
authors: Liu
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D011725:Pyridines; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil; C104201:gimeracil