title: Pre-treatment evaluation of 5-fluorouracil degradation rate: association of poor and ultra-rapid metabolism with severe toxicity in a colorectal cancer patients cohort.
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.
authors.affiliation: Oncology Unit, Sant'Andrea Hospital, Rome, Italy.|Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Mazzuca
authors.affiliation: Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Borro
authors.affiliation: Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Botticelli
authors.affiliation: Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Eva
authors.initials: E
authors.lastname: Mazzotti
authors.affiliation: Department of Clinical Oncology, Policlinico Umberto I, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Marchetti
authors.affiliation: Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Gentile
authors.affiliation: Department of Clinical Oncology, Policlinico Umberto I, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: La Torre
authors.affiliation: Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Lionetto
authors.affiliation: Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Simmaco
authors.affiliation: Oncology Unit, Sant'Andrea Hospital, Rome, Italy.|Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.|Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Marchetti
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000633:toxicity; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology* / Q000633:toxicity; D005500:Follow-Up Studies; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D042943:Dihydrouracil Dehydrogenase (NADP); C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); C000600377:TYMS protein, human; D013940:Thymidylate Synthase; D005472:Fluorouracil
keywords: 5-fluorouracil degradation rate; DPYD; colorectal cancer; fluorouracil toxicity prediction; polymorphisms