Naslov (srp)

Farmakogenetički markeri odgovora na terapiju tiopurinskim lekovima, metotreksatom i vinkristinom kod dece sa akutnom limfoblastnom leukemijom : doktorska disertacija

Autor

Ristivojević, Bojan, 1985-

Doprinosi

Zukić, Branka, 1976-
Kotur, Nikola, 1983-
Čolović, Nataša, 1973-
Brkušanin, Miloš, 1987-
Brajušković, Goran, 1968-

Opis (srp)

Akutna limfoblastna leukemija (ALL) je najčešći malignitet dečjeg doba. Napredak ulečenju usmeren je ka smanjenju pojave neželjenih efekata terapije, primenom principafarmakogenetike.U ovoj studiji istraživanje je bilo usmereno ka otkrivanju farmakogenetičkih ifarmakotranskriptomskih markera odgovora na lekove koji su okosnica terapijskih protokola lečenjadece obolele od ALL (tiopurinski lekovi, metotreksat i vinkristin).Analizirani su uzorci krvi i koštane srži 139 dece sa ALL. Varijante u ispitivanim genimadetektovane su metodom PCR-a i Sangerovim sekvenciranjem. Nivo ekspresije NUDT15 umononuklearnim ćelijama određen je real-time PCR-om. Korelacija farmakomarkera sa kliničkimparametrima 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 neželjenihefekata terapije tiopurinskim lekovima. U ispitivanoj grupi detektovano je 5 varijanti u genuNUDT15 koje nemaju patogeni efekat. Varijanta rs4149056 u genu SLCO1B1 je izučavana kaomarker farmakokinetike i toksičnosti metotreksata. U ovoj studiji nije potvrđen njen klinički značaj.Analiziran je farmakogenetički potencijal varijanti u genima CYP3A5, CEP72, ACTG1, MIR3117 iMIR4481 kao markera odgovora na terapiju vinkristinom. Nije potvrđena korelacija ovih varijantisa nastankom perifernih neuropatija kod dece sa ALL. Razvijen je predikcioni model zahepatotoksičnost izazvanu metotreksatom, zasnovan na poligenskom skoru rizika.Ova studija je doprinela znanjima koja vode ka personalizaciji lečenja dece obolele od ALL.

Opis (srp)

Molekularna biologija eukariota - Molekularna genetika / Datum odbrane: 03.04.2023.

Opis (eng)

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 theprinciples of pharmacogenetics.The aim of this study was to discover pharmacogenetic and pharmacotranscriptomicmarkers of response to drugs that are the backbone of therapeutic protocols for the treatment ofchildren with ALL (thiopurine drugs, methotrexate and vincristine).Blood and bone marrow samples of 139 children with ALL were analysed. Variants in thetested genes were detected by PCR and Sanger sequencing. The expression level of NUDT15 inmononuclear cells was determined by real-time PCR. The correlation of pharmacomarkers withclinical parameters was performed using statistical tests.The response to the investigated drugs was evaluated in retrospective clinical studies. It wasshown that the level of NUDT15 expression at the presentation of the disease does not correlatewith the occurrence of side effects of thiopurine drug therapy. In this study 5 variants in theNUDT15 gene were detected, which do not have a pathogenic effect. The rs4149056 variant in theSLCO1B1 gene was assessed as a marker of methotrexate pharmacokinetics and toxicity. Its clinicalsignificance 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 wasanalysed. The correlation of these variants with the onset of peripheral neuropathies in children withALL has not been confirmed. A predictive model for methotrexate-induced hepatotoxicity based onthe polygenic risk score was developed.This study contributed to the knowledge that leads to the personalization of the treatment ofchildren with ALL.

Jezik

srpski

Datum

2023

Licenca

Ovo delo je licencirano pod uslovima licence
Creative Commons CC BY-NC-ND 3.0 AT - Creative Commons Autorstvo - Nekomercijalno - Bez prerada 3.0 Austria License.

http://creativecommons.org/licenses/by-nc-nd/3.0/at/legalcode

Predmet

OSNO - Opšta sistematizacija naučnih oblasti, Molekularna genetika

farmakogenetika, dečja akutna limfoblastna leukemija, tiopurinski lekovi, metotreksat, vinkristin, poligenski skor rizika, nudiks hidroksilaza 15 (NUDT15), vinkristinom indukovana periferna neuropatija (VIPN)

577.2:616.155.392(043.3)

OSNO - Opšta sistematizacija naučnih oblasti, Molekularna genetika

pharmacogenetics, childhood acute lymphoblastic leukemia, thiopurine drugs, methotrexat, vincristine, polygenic risc score, nudix hydroxylase 15 (NUDT15), vincristine- induced peripheral neuropathy (VIPN)