Pre-treatment evaluation of 5-fluorouracil degradation rate: association of poor and ultra-rapid metabolism with severe toxicity in a colorectal cancer patients cohort
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Federica Mazzuca1,2, Marina Borro3, Andrea Botticelli2, Eva Mazzotti2, Luca Marchetti4, Giovanna Gentile5, Marco La Torre4, Luana Lionetto5, Maurizio Simmaco3, Paolo Marchetti1,2,3
1Oncology Unit, Sant’Andrea Hospital, Rome, Italy
2Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy
3Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy
4Department of Clinical Oncology, Policlinico Umberto I, Rome, Italy
5Istituto Dermopatico dell’Immacolata-IRCCS, Rome, Italy
Eva Mazzotti, e-mail: [email protected]
Keywords: 5-fluorouracil degradation rate, fluorouracil toxicity prediction, DPYD, colorectal cancer, polymorphisms
Received: December 08, 2015 Accepted: February 15, 2016 Published: March 08, 2016
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.
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