Značaj polimorfizama u genima koji kodiraju enzime uključene u metabolizam metotreksata u dece sa akutnom limfoblastnom leukemijom

Abstract

Uvod: Akutna limfoblastna leukemija (ALL) je najčešća maligna bolest u pedijatrijskom uzrastu. Primenom savremenih protokola postignuto je preživljavanje u skoro 90% obolele dece. Najnovija istraživanja su usmerena ka farmakogenetici, sa ciljem da se smanji toksičnost primenjenih lekova, koji mogu biti uzrok smrtnog ishoda ili dugoročnih komplikacija koje utiču na kvalitet života po završetku lečenja. Na osnovu farmakogenetskih ispitivanja se može vršiti modulacija terapije, odnosno odrediti dozni režim lekova koji je prilagođen svakom pacijentu. Metotreksat (engl. Methotrexate – MTX) je antagonist folata i jedan je od ključnih lekova u terapijskim protokolima za pedijatrijsku ALL. Delotvoran je u postizanju i održavanju remisije u dece sa ALL, ali su odavno poznata neželjena dejstva koja njegova primena može da izazove. Ciljevi: Sastoje se u ispitivanju uticaja gena koji kodiraju enzime uključene u metabolizam MTX i njihovih varijanti na tok i ishod lečenja dece obolele od ALL. Na prvom mestu cilj doktorske disertacije je bio da se utvrdi učestalost varijanti c.677C>T i c.1289A>C u genu za MTHFR, -680 C>A, -675 A>G, -556 T>C, -464 A>T i -317 A>G u genu za DFHR, c.80G>A u genu za SLC19A1, 28 bp tandemski ponovak i 6 bp delecija u genu za TYMS. Učestalost polimorfizama je ispitana u dece obolele od ALL i kontrolnoj grupi i učinjena je uporedna analiza incidence u bolesnih i zdravih osoba. Nezavisno od farmakogenetičkih markera, cilj je bio da se ispita farmakokinetika (engl. Pharmacokinetics – PK) MTX i da se dobijeni rezultati koreliraju sa navedenim polimorfizmima. Takođe, praćena je klinička i laboratorijska toksičnost terapije MTX i istraženo je da li postoji povezanost pojedinačnih ili udruženih varijanti u ispitanim genima sa povećanom toksičnošću MTX. Na osnovu ispitanih parametara ideja je bila da se utvrdi da li postoji modulacija terapije i u kojoj meri kod prisustva pojedinačnih i/ili udruženih genetičkih varijanti. Krajnji cilj je bio da se utvrdi uticaj navednih polimorfizama u genima za DFHR, MTHFR, SLC19A1 i TYMS na ishod dece obolele od ALL...

Objective: Acute lymphoblastic leukemia (ALL) is the most common malignant disease among children and adolescents. Contemporary protocols ensure survival rate in almost 90% of affected children. The latest research is directed towards pharmacogenetics, in order to reduce the toxicity of applied drugs, which may be the cause of death or long-term complications that affect the quality of life after completion of treatment. Pharmacogenetic studies are offering basis for therapy modulation, by changing drugs dosage regimen in order to tailor the therapy according to needs of each affected patient. Methotrexate (MTX) is a folate antagonist and is one of the key drugs in therapeutic protocols for pediatric ALL. MTX is effective in achieving and maintaining remission in children with ALL, but possible adverse side effects of its use are already well known. Aims: The most important goal was to test the influence of genes encoding enzymes involved in the metabolism of MTX and their variants on the course and outcome of children with ALL. First and foremost objective of the doctoral dissertation was to determine the frequency of variants c.677C>T and c.1289A>C in MTHFR gene, - 680 C>A, -675 A>G, -556 T>C, -464 A>T and -317 A>G in DFHR gene, c.80G> A in SLC19A1 gene, 6 bp deletion and 28 bp tandem repeats in TYMS gene. The incidence of polymorphisms in children with ALL and a control group was explored and afterwards compared in order to investigate eventual different pattern between pediatric ALL patients and healthy individuals. The goal was to investigate the pharmacokinetics (PK) and clinical and laboratory toxicity during MTX treatment and then to correlate with the aforementioned polymorphisms with the idea to explore whether there is a relationship of single or associated variants in the selected genes with already established MTX toxicity. The aim was to investigate the extent of therapy modulation in presence of individual and/or associated genetic variants by summarizing all results related to MTX toxicity. The ultimate goal was to determine the effect of aforementioned polymorphisms in genes MTHFR, DFHR, SLC19A1 and TYMS to the outcome of children with ALL...