Uloga farmakogenetike i polimorfizma gena za dihidropirimidin-dehidrogenazu (DPYD) u personaliziranom liječenju 5-fluorouracilom

Cilj istraživanja: Cilj ovog rada jest sistematično i pregledno prikazati farmakogenetiku 5-fluorouracila (5-FU-a) i polimorfizme gena za dihidropirimidin-dehidrogenazu (DPYD) koji utječu na učinkovitost i sigurnost terapije 5-FU-om. Time bi se zdravstvenim djelatnicima olakšala odluka o odbacivanju ili odabiru i individualizaciji terapije 5-FU-om prema određenom genotipu onkološkog pacijenta kojem je potrebno liječenje 5-FU-om, a sve u svrhu sigurnog liječenja i prevencije teških nuspojava i smrti. Materijali i metode: Pretražena je znanstvena literatura objavljena u bazama podataka Medline i PubMed u posljednjih 10 godina. Također su pretražene publikacije stručnih udruga i institucija, baze lijekova te ostali znanstveni izvori. Komentirane su terapijske smjernice za primjenu i individualizaciju terapije 5-FU-om (polimorfizmi gena DPYD-a c.1905+1G>A, c.1679T>G, c.2846A>T i c.1236G>A). Opisana je i moguća važnost drugih polimorfizama DPYD-a (c.496A>G, c.85T>C i c.2194G>A) te su navedene i međuetničke i međurasne razlike u učestalosti nekih polimorfizama DPYD-a. Izneseni su i podaci o mogućnostima individualizacije terapije 5-FU-om u Hrvatskoj, tj. informacije o laboratorijima koji provode genotipizaciju DPYD-a. Rezultati: Aktivnost enzima dihidropirimidin-dehidrogenaze (DPD) ograničavajući je faktor brzine metabolizma 5-FU-a i podliježe velikoj varijabilnosti stoga su bolesnici s nedostatkom DPD-a pod povećanim rizikom od toksičnosti povezane s fluoropirimidinima. Smjernice za genotipizaciju DPYD-a i doziranje fluoropirimidina izdane od strane CPIC-a (Clinical Pharmacogenetics Implementiation Consortium) uključuju 4 varijante gena DPYD za koje je dokazano da smanjuju aktivnost DPD-a (c.1905+1G>A, c.1679T>G, c.2846A>T i c.1236G>A). Proučavani su i drugi polimorfizmi (c.496A>G, c.85T>C i c.2194G>A) te većina rezultata govori u prilog smanjene aktivnosti enzima DPD-a uslijed njihove prisutnosti. U talijanskoj randomiziranoj studiji Three or six colon adjuvant (TOSCA) ozbiljne i teške nuspojave zabilježene su u 38,2 % ispitanika (nositelji mutacija c.2194G˃A, c.1905+1G˃A i c.496A˃G). Kliničko ispitivanje Pan-European Trials in an Alimentary Tract Cancer (PETACC-8) također potvrđuje gore navedeno jer je u istom utvrđeno da su se ozbiljne nuspojave javljale u 85,7 % nositelja mutacije c.2846A˃T i 60,8 % nositelja mutacije c.2194G˃A. Božina i suradnici su zabilježili ozbiljne nuspojave u čak 56,3 % ispitanika (nositelji varijanti c.496A>G ili c.2194G>A) dok mutacija c.85T>C nije bila povezana s razvojem ozbiljnih nuspojava. U radu Henricks i suradnika pokazano je da je predterapijsko testiranje isplativo ili barem ne predstavlja dodatni trošak za zdravstveni sustav. Zaključak: Nositelji inaktivirajućih alela DPYD-a imaju značajno veći rizik ozbiljnih nuspojava. Zbog toga su izdane preporuke za obavljanje genetičkog testiranja DPYD-a ili mjerenja aktivnosti DPD-a prije primjene lijeka. Time se olakšava odluka o odabiru 5-FU-a i doze prema pacijentovom genetičkom profilu te se smanjuju troškovi zdravstvene zaštite jer se poboljšava liječenje i smanjuju rizici koji, osim što predstavljaju teško stanje i patnju za pacijenta, za zdravstveni sustav predstavljaju i trošak u zbrinjavanju nuspojava liječenja.Objectives: This thesis aim is to systematically and clearly present the pharmacogenetics of 5-fluorouracil (5-FU) and DPYD gene polymorphisms that affects the efficacy and safety of 5-FU therapy. Healthcare professionals would find it easier to decide whether to reject or select and individualize 5-FU therapy according to the specific genotype of an oncology patient in need of 5-FU treatment, thus providing the safe treatment and prevention of severe side effects and death. Materials and methods: The scientific literature in databases Medline and PubMed in the last 10 years has been searched. Publications of professional associations and institutions, drug databases and other scientific sources also were searched. Therapeutic guidelines for the application and individualization of 5-FU therapy are commented (the most important polymorphisms of the DPYD gene c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A). The possible importance of other DPYD polymorphisms (c.496A>G, c.85T>C and c.2194G>A) is also described, and interethnic and interracial differences in the frequency of some DPYD polymorphisms are listed. Information on laboratories that perform DPYD genotyping and the possibilities of individualization of 5-FU therapy in Croatia are also presented. Results: DPD activity is a limiting factor in the rate of 5-FU metabolism and is subject to high variability, therefore patients with DPD deficiency are at increased risk of toxicity related to fluoropyrimidines. Guidelines for DPYD genotyping and fluoropyrimidine dosing were published by CPIC (Clinical Pharmacogenetics Implementation Consortium), which include 4 variants that have been shown to reduce DPD activity (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G A). Other polymorphisms (c.496A>G, c.85T>C and c.2194G>A) have been studied in various studies and most of the results speak in favor of reduced activity of DPD enzymes due to their presence. In the Italian randomized study Three or six colon adjuvant (TOSCA), serious and severe side effects were reported in 38.2 % of subjects (carriers of mutations c.2194G˃A, c.1905+1G˃A and c.496A˃G). Clinical trial Pan-European Trials in an Alimentary Tract Cancer (PETACC-8) also confirms the above mentioned as it was found that serious side effects occurred in 85.7 % of carriers of mutation c.2846A˃T and 60.8 % of carriers of mutation c.2194G˃А. Božina and co-workers reported serious side effects in 56.3 % of subjects (carriers of c.496A>G or c.2194G>A) while c.85T>C mutation was not associated with the development of serious side effects. The work of Henricks and co-workers has shown that pre-therapy testing is cost-effective or at least does not represent an additional cost to the health care system. Conclusion: Carriers of DPYD inactivating alleles have a significantly higher risk of serious side effects. Therefore, recommendations have been issued to perform genetic testing for DPYD or to measure DPD activity prior to drug administration. This facilitates the decision on the choice of 5-FU and dose individualization according to the patient's genetic profile and reduces health care costs because it improves treatment and reduces risks that represents suffering for the patient and cost the health system