Uloga polimorfizama gena dihidropirimidin-dehidrogenaze i UDP-glukuronil-transferaze u toksičnosti kemoterapije fluoropirimidinima i irinotekanom [The role of dihydropyrimidine-dehydrogenase and UDP-glucuronyl transferase polymorphisms in fluoropyrimidine and irinotecan toxicity]

Bilić, Ivan (2016) Uloga polimorfizama gena dihidropirimidin-dehidrogenaze i UDP-glukuronil-transferaze u toksičnosti kemoterapije fluoropirimidinima i irinotekanom [The role of dihydropyrimidine-dehydrogenase and UDP-glucuronyl transferase polymorphisms in fluoropyrimidine and irinotecan toxicity]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Chemotherapy with fluoropyrimidines (5-FU, capecitabine) is the foundation of oncological treatment for patients with gastrointestinal tumors (colorectal cancer in particular), as well as other types of solid malignancies. Dihydropirimidine-dehydrogenase (DPD) is the rate-limiting enzyme of the fluoropyrimidine methabolism, responsible for bulk degradation of injected drug (up to 90%). DPYD gene may contain polymorphisms with potentially lethal functional consequences, but risk-level varies considerably according to the type of polymorphism. Patients with enzyme-deficiency may have elevated drug and metabolite levels, and increased risk for toxic adverse events. In this single-center, case-control designed study fluoropyrimidine and irinotecan-treated patients were sampled (N=305), five DPYD-polymorphisms (DPYD*2A, *13, c.2846A>T, c.1236G>A and c.496A>G) and UGT1A1*28 were analyzed. We stratified subjects according to the toxicity grade (observed group – grade 3 and 4; control group – grade 0, 1 and 2). Frequencies of tested genetic traits were established. Carriers of DPYD polymorphism and UGT1A1*28 variant had a statistically significant increase in the risk for toxic side effects. The results point to significant association as well as predictive value of the mutation status with chemotherapy toxicity. Subjects with higer toxicity grades developed adverse effects more rapidly and accumulated greater total number of events per capita.

Abstract in Croatian

Kemoterapija fluoropirimidinima je temelj onkološkog liječenja bolesnika s tumorima probavnog trakta. Dihidropirimidin-dehidrogenaza (DPD) je najvažniji enzim metaboličkog puta fluoropirimidina, odgovoran za razgradnju većine unešene tvari (do 90%). Polimorfizmi gena za DPD mogu značajno utjecati na sniženje enzimske aktivnosti i povećanje rizika za nastanak toksičnih nuspojava uz primjenu kemoterapije. U istraživanju je genotipizacijom određena učestalost polimorfizama gena za dihidropirimidin-dehidrogenazu (DPYD*2A, *13, c.2846A>T, c.1236G>A i c.496A>G) na uzorku (N=305) onkoloških bolesnika liječenih kemoterapijskim protokolima temeljenim na fluoropirimidinima. Također je testirana prisutnost polimorfizma UDP-glikozil transferaze (UGT1A1*28) u podskupini bolesnika koji su uz fluoropirimidine primali i irinotekan, obzirom na poznatu važnost disfunkcije UGT na metabolizam irinotekana. Ispitanici su podijeljeni prema jačini nuspojava u promatranu skupinu (stupanj 3 i 4) i kontrolu (stupanj 0, 1 i 2). Kod bolesnika s mutiranim genom DPYD kao i polimorfizmom UGT1A1*28 pokazano je statistički signifikantno povećanje rizika za nastanak toksičnih nuspojava. Ispitanici u promatranoj skupini nuspojave su razvijeli brže (prosječno iza 2. ciklusa, naspram 3. ciklusa u kontrolnoj skupini). Također, ukupni broj nuspojava po ispitaniku je veći u promatranoj skupini (prosječno 3 vs. 1,7).

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