Pre-treatment evaluation of 5-fluorouracil degradation rate: Association of poor and ultra-rapid metabolism with severe toxicity in a colorectal cancer patients cohort

Federica Mazzuca, Marina Borro, Andrea Botticelli, Eva Mazzotti, Luca Marchetti, Giovanna Gentile, Marco La Torre, Luana Lionetto, Maurizio Simmaco, Paolo Marchetti

Research output: Contribution to journalArticle

Abstract

Despite the wide use of 5-fluorouracil-based chemotherapy, development of severe toxicity that follow the treatment is not a rare event. The efforts to establish pretreatment tools for toxicity prediction, led to the development of various pharmacogenetic and biochemical assays, mainly targeted to assess the activity level of dihydropyrimidine dehydrogenase (DPD), the main metabolizing enzyme for 5-fluorouracil. Using peripheral blood mononuclear cells, we developed a biochemical assay, that is not limited to the evaluation of DPD activity, but determines the net result of all the enzymatic transformation of 5FU, in terms of the amount of drug consumed by the cells in a time unit. This parameter, named 5-fluorauracil degradation rate, presents a normal distribution inside the population and highlight the presence of an ultra-rapid metabolizers class of subjects, besides the expected poor metabolizers class. Here we will show that, in a colorectal cancer patient cohort, both poor and ultra-rapid metabolizers have significantly increased the risk of developing severe toxicity (grade3-4). Patient stratification depending on the individual 5-fluorouracil degradation rate allows to identify a 10% of the overall population at high risk of developing severe toxicity, compared to the 1.3% (as assessed in the Italian population) identified by the most commonly employed pharmacogenetic test, including the DPD polymorphism IVS14+1G > A.

Original languageEnglish
Pages (from-to)20612-20620
Number of pages9
JournalOncotarget
Volume7
Issue number15
DOIs
Publication statusPublished - Apr 12 2016

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Keywords

  • 5-fluorouracil degradation rate
  • Colorectalcancer
  • DPYD
  • Fluorouracil toxicity prediction
  • Polymorphisms

ASJC Scopus subject areas

  • Oncology

Cite this

Mazzuca, F., Borro, M., Botticelli, A., Mazzotti, E., Marchetti, L., Gentile, G., La Torre, M., Lionetto, L., Simmaco, M., & Marchetti, P. (2016). Pre-treatment evaluation of 5-fluorouracil degradation rate: Association of poor and ultra-rapid metabolism with severe toxicity in a colorectal cancer patients cohort. Oncotarget, 7(15), 20612-20620. https://doi.org/10.18632/oncotarget.7991