Farmakogenetički markeri odgovora na terapiju tiopurinskim lekovima, metotreksatom i vinkristinom kod dece sa akutnom limfoblastnom leukemijom
Pharmacogenetic markers of response to therapy with thiopurine drugs, methotrexate, and vincristine in children with acute lymphoblastic leukemia
Author
Ristivojević, BojanMentor
Zukić, BrankaCommittee members
Brkušanin, MilošBrajušković, Goran
Čolović, Nataša
Kotur, Nikola
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Show full item recordAbstract
Akutna limfoblastna leukemija (ALL) je najčešći malignitet dečjeg doba. Napredak u
lečenju usmeren je ka smanjenju pojave neželjenih efekata terapije, primenom principa
farmakogenetike.
U ovoj studiji istraživanje je bilo usmereno ka otkrivanju farmakogenetičkih i
farmakotranskriptomskih markera odgovora na lekove koji su okosnica terapijskih protokola lečenja
dece obolele od ALL (tiopurinski lekovi, metotreksat i vinkristin).
Analizirani su uzorci krvi i koštane srži 139 dece sa ALL. Varijante u ispitivanim genima
detektovane su metodom PCR-a i Sangerovim sekvenciranjem. Nivo ekspresije NUDT15 u
mononuklearnim ćelijama određen je real-time PCR-om. Korelacija farmakomarkera sa kliničkim
parametrima vršena je statističkim testovima.
Odgovor na ispitivane lekove procenjivan je u retrospektivnim kliničkim studijama.
Pokazano je da nivo ekspresije NUDT15 na prezentaciji bolesti ne korelira sa pojavom neželjenih
efekata terapije tiopurinskim lekovima. U ispitivanoj grupi detektovano je 5 va...rijanti u genu
NUDT15 koje nemaju patogeni efekat. Varijanta rs4149056 u genu SLCO1B1 je izučavana kao
marker farmakokinetike i toksičnosti metotreksata. U ovoj studiji nije potvrđen njen klinički značaj.
Analiziran je farmakogenetički potencijal varijanti u genima CYP3A5, CEP72, ACTG1, MIR3117 i
MIR4481 kao markera odgovora na terapiju vinkristinom. Nije potvrđena korelacija ovih varijanti
sa nastankom perifernih neuropatija kod dece sa ALL. Razvijen je predikcioni model za
hepatotoksičnost izazvanu metotreksatom, zasnovan na poligenskom skoru rizika.
Ova studija je doprinela znanjima koja vode ka personalizaciji lečenja dece obolele od ALL.
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy.
Treatment progress is aimed at reducing the occurrence of side effects of therapy, by applying the
principles of pharmacogenetics.
The aim of this study was to discover pharmacogenetic and pharmacotranscriptomic
markers of response to drugs that are the backbone of therapeutic protocols for the treatment of
children with ALL (thiopurine drugs, methotrexate and vincristine).
Blood and bone marrow samples of 139 children with ALL were analysed. Variants in the
tested genes were detected by PCR and Sanger sequencing. The expression level of NUDT15 in
mononuclear cells was determined by real-time PCR. The correlation of pharmacomarkers with
clinical parameters was performed using statistical tests.
The response to the investigated drugs was evaluated in retrospective clinical studies. It was
shown that the level of NUDT15 expression at the presentation of the disease does not correlate
with the occurrence of side e...ffects of thiopurine drug therapy. In this study 5 variants in the
NUDT15 gene were detected, which do not have a pathogenic effect. The rs4149056 variant in the
SLCO1B1 gene was assessed as a marker of methotrexate pharmacokinetics and toxicity. Its clinical
significance was not confirmed in this study. The pharmacogenetic potential of variants in CYP3A5,
CEP72, ACTG1, MIR3117 and MIR4481 genes as markers of response to vincristine therapy was
analysed. The correlation of these variants with the onset of peripheral neuropathies in children with
ALL has not been confirmed. A predictive model for methotrexate-induced hepatotoxicity based on
the polygenic risk score was developed.
This study contributed to the knowledge that leads to the personalization of the treatment of
children with ALL.