Značaj polimorfizama u genima koji kodiraju enzime uključene u metabolizam metotreksata u dece sa akutnom limfoblastnom leukemijom
The significance of polymorphisms in the genes encoding enzymes involved in the metabolism of methotrexate in children with acute lymphoblastic leukemia
Докторанд
Lazić, JelenaМентор
Krstovski, NadaЧланови комисије
Janić, DraganaDokmanović, Lidija
Pavlović, Sonja
Метаподаци
Приказ свих података о дисертацијиСажетак
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
prv...om 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...
Факултет:
Универзитет у Београду, Медицински факултетДатум одбране:
21-09-2016Пројекти:
- Ретке болести: молекуларна патофизиологија, дијагностички и терапијски модалитети и социјални, етички и правни аспекти (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41004)