title: Human uridine phosphorylase-1 inhibitors: a new approach to ameliorate 5-fluorouracil-induced intestinal mucositis.
abstract: OBJECTIVE
  5-fluorouracil (5-FU) has been broadly used to treat solid tumors for more than 50 years. One of the major side effects of fluoropyrimidines therapy is oral and intestinal mucositis. Human uridine phosphorylase (hUP) inhibitors have been suggested as modulators of 5-FU toxicity. Therefore, the present study aimed to test the ability of hUP blockers in preventing mucositis induced by 5-FU.
  
  
  METHODS
  We induced intestinal mucositis in Wistar rats with 5-FU, and the intestinal damage was evaluated in presence or absence of two hUP1 inhibitors previously characterized. We examined the loss of weight and diarrhea following the treatment, the villus integrity, uridine levels in plasma, and the neutrophil migration by MPO activity.
  
  
  RESULTS
  We found that one of the compounds, 6-hydroxy-4-methyl-1H-pyridin-2-one-3-carbonitrile was efficient to promote intestinal mucosa protection and to inhibit the hUP1 enzyme, increasing the uridine levels in the plasma of animals. However, the loss of body weight, diarrhea intensity or neutrophil migration remained unaffected.
  
  
  CONCLUSIONS
  Our results bring support to the hUP1 inhibitor strategy as a novel possibility of prevention and treatment of mucositis during the 5-FU chemotherapy, based on the approach of uridine accumulation in plasma and tissues.
authors: Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF) Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.
authors: Daiana
authors: D
authors: Renck
authors: André A
authors: AA
authors: Santos
authors: Pablo
authors: P
authors: Machado
authors: Guilherme O
authors: GO
authors: Petersen
authors: Tiago G
authors: TG
authors: Lopes
authors: Diógenes S
authors: DS
authors: Santos
authors: Maria M
authors: MM
authors: Campos
authors: Luiz A
authors: LA
authors: Basso
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects*; D006801:Humans; D007410:Intestinal Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052016:Mucositis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011728:Pyridones / Q000627:therapeutic use*; D017208:Rats, Wistar; D014529:Uridine / Q000097:blood; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors*
chemical_list: C000599297:6-hydroxy-4-methyl-1H-pyridin-2-one-3-carbonitrile; D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D011728:Pyridones; D009195:Peroxidase; D014543:Uridine Phosphorylase; D005472:Fluorouracil; D014529:Uridine