Author/Editor		Šmid, Alenka; Jazbec, Janez; Mlinarič-Raščan, Irena
Title		Farmakogenetski označevalci v terapiji akutne limfoblastne levkemije pri otrocih
Translated title		Pharmacogenetic markers in the therapy of childhood acute lymphoblastic leukemia
Type		članek
Vol. and No.		Letnik 88, št. 5/6
Publication year		2019
Volume		str. 235-248
ISSN		1318-0347 - Zdravniški vestnik : glasilo Slovenskega zdravniškega društva : Slovenian medical journal
Language		slv
Abstract		Posamezniku prilagojeno zdravljenje predstavlja sodoben koncept v medicinski praksi, ki temelji na spoznanju, da se posamezniki različno odzivajo na določeno terapijo. Osrednji element prilagojenega zdravljenja predstavljajo biološki označevalci, med katere uvrščamo tudi genetske. Med najuspešnejše primere uvajanja farmakogenetskih označevalcev v klinično prakso z namenom prilagajati odmerjanje zdravil posamezniku sodi zdravljenje akutne limfoblastne levkemije (ALL). Ta predstavlja približno 80 % vseh oblik levkemije, ki se pojavijo pri otrocih, mlajših od 15 let, kar jo uvršča na prvo mesto po pogostosti raka v otroštvu. V zadnjih desetletjih smo bili priča izjemnemu napredku na področju zdravljenja ALL, kljub temu pa je le-to še vedno neuspešno pri nekaterih bolnikih bodisi zaradi toksičnih stranskih učinkov, bodisi zaradi neučinkovitosti uporabljenih zdravil, kar vodi v ponovitev bolezni. Dodaten problem predstavljajo še dolgoročni toksični učinki kemoterapije, ki se lahko pojavijo tudi več let po zaključenem zdravljenju. Prav iz teh razlogov se je v zadnjih letih veliko študij posvetilo odkrivanju bioloških označevalcev, na podlagi katerih bi lahko zdravljenje prilagodili posamezniku in s tem izboljšali njegovo učinkovitost in varnost. Najbolje proučeni so genetski dejavniki, povezani s toksičnostjo 6-merkaptopurina (6-MP), ki predstavlja temelj vzdrževalnega zdravljenja ALL. Encim tiopurin-S-metiltransferaza (TPMT) igra poglavitno vlogo pri deaktiviranju tiopurinov in v veliki meri vpliva na razlike v odzivu posameznikov na zdravljenje. Znano je, da so za znižane encimske aktivnosti v največji meri odgovorni polimorfizmi v genu za TPMT, vendar je ujemanje med genotipom in encimsko aktivnostjo nepopolno. V zadnjem desetletju so identificirali nove farmakogenetske označevalce, povezane s toksičnostjo 6-MP in drugih zdravil, ki se uporabljajo za zdravljenje otroške ALL, vendar se še ne uporabljajo v klinični praksi.Personalised medicine is a contemporary concept in medical practice, based on the observation that individuals respond differently to a particular therapy. Biomarkers, which include genetic markers, are a central element in the development of personalised medicine. Acute lymphoblastic leukaemia (ALL) therapy is among the most successful examples of the implementation of pharmacogenetic markers into clinical practice in order to adjust the dosage of drugs to an individual. ALL accounts for approximately 80% of all forms of leukaemia occurring in children under the age of 15 years, making it the most common childhood cancer. Despite drastic improvements in the treatment of childhood ALL over the past decades, treatment is still unsuccessful in some patients either due to toxic effects, or due to the inefficacy of the drugs used, which leads to a recurrence of the disease. An additional problem is associated with the long-term toxic effects of chemotherapy, which may occur several years after the treatment has been completed. In order to improve safety and efficacy, numerous studies have been performed aiming to identify biomarkers which would enable tailoring treatment to the individual patient and improve treatment%s efficacy and safety. Of these, the genetic factors associated with the toxicity of 6-mercaptopurine (6-MP), which is the cornerstone of maintenance treatment of ALL, have been studied most thoroughly. Thiopurine S- methyltransferase (TPMT) is a polymorphic enzyme which plays a major role in the deactivation of thiopurines and to a large extent accounts for the differences in individuals% response to treatment. It has long been known that polymorphisms in the TPMT gene are largely responsible for reduced enzymatic activities, but numerous studies have shown that the accordance between genotype and enzyme activity is incomplete. In many studies published over the past decade, new pharmacogenetic markers have been associated with toxic effects of 6-MP as well as other drugs used for ALL therapy; however, they are not yet used in clinical practice.
Descriptors		Levkemija
Keywords		posamezniku prilagojeno zdravljenje farmakogenetika akutna limfoblastna levkemija tiopurin-S-metiltransferaza tiopurini