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Human uridine phosphorylase-1 inhibitors: a new approach to ameliorate 5-fluorouracil-induced intestinal mucositis

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Summary

Purpose 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. Conclusion 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.

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Abbreviations

5-FU:

5-fluorouracil

DMSO:

dimethyl-sulfoxide

FUTP:

fluorouridine 5’-triphosphate

hUP:

human uridine phosphorylase

MPO:

myeloperoxidase

UTP:

uridine triphosphate

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Acknowledgments

This work was supported by the National Institute of Science and Technology on Tuberculosis, (DECIT/SCTIE/MS-MCT-CNPq-FNDCT-CAPES) awarded to D.S.S. and L.A.B.. L.A.B. and D.S.S. also acknowledge financial support awarded by FAPERGS-CNPq-PRONEX-2009. L.A.B.., D.S.S. and M.M.C. are Research Career Awardees of the National Research Council of Brazil (CNPq). D.R. and G.O.P. are recipients of a PhD scholarship awarded by CNPq and A.A.S.Jr. is recipient of a PhD scholarship awarded by CAPES.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 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

    Daiana Renck, Pablo Machado, Guilherme O. Petersen, Diógenes S. Santos & Luiz A. Basso

  2. Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil

    Daiana Renck, André A. Santos Jr, Pablo Machado, Guilherme O. Petersen, Diógenes S. Santos & Luiz A. Basso

  3. Instituto de Toxicologia e Farmacologia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil

    André A. Santos Jr & Maria M. Campos

  4. Instituto de Pesquisas Biomédicas (IPB), Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Tiago G. Lopes

  5. Faculdade de Odontologia, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil

    Maria M. Campos

Authors
  1. Daiana Renck
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  2. André A. Santos Jr
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  3. Pablo Machado
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  4. Guilherme O. Petersen
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  6. Diógenes S. Santos
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  7. Maria M. Campos
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  8. Luiz A. Basso
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Corresponding author

Correspondence to Maria M. Campos.

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Renck, D., Santos, A.A., Machado, P. et al. Human uridine phosphorylase-1 inhibitors: a new approach to ameliorate 5-fluorouracil-induced intestinal mucositis. Invest New Drugs 32, 1301–1307 (2014). https://doi.org/10.1007/s10637-014-0135-0

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  • DOI: https://doi.org/10.1007/s10637-014-0135-0

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