Individualization of Thiopurine Therapy: Thiopurine
            <i>S</i>
            -Methyltransferase and Beyond

Karas-Kuzelicki, Natasa; Mlinarič-Raščan, Irena

doi:10.2217/pgs.09.78

Cited by 38 publications

(27 citation statements)

References 87 publications

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“…TPMT is a S-Adenosyl methionine (SAM)-dependent methyltransferse that catalyses the deactivation of thiopurine drugs, such as 6-MP and 6-thioguanine (31). If the TPMT activity is low (such as in the presence of polymorphisms in the TPMT gene), this will result in high concentrations of cytotoxic thioguanine nucleotides (TGN) due to decreased conversion of thiopurine drugs to inactive methylated metabolites (31). The toxic effects of 6-MP on bone and bone cells have been demonstrated in vitro (5) and in vivo (7).…”

Section: Discussionmentioning

confidence: 99%

Risk factors for symptomatic osteonecrosis in childhood ALL: A retrospective study of a Slovenian pediatric ALL population between 1970 and 2004

Karas-Kuzelicki¹,

Mencej-Bedrač²,

Jazbec³

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Treatment induced non-traumatic osteonecrosis (ON) has been reported increasingly in children treated for acute lymphoblastic leukemia (ALL). Several risk factors for ON have been identified in childhood cancer patients; however, their diagnostic and prognostic power is limited and the etiology of the disease remains unclear. Therefore, a continuous effort is focused on the identification of additional ON risk factors. We performed a retrospective study of 313 childhood ALL patients to test the association between the ON occurrence in children receiving ALL therapy and common polymorphisms in potential target genes: Thiopurine S-methyltransferase (TPMT; 460G>A, 719A>G), 5,10-methylenetetrahydrofolate reductase (MTHFR; 677C>T, 1298A>C), estrogen receptor alpha 1 (ESR1; XbaI) and collagen type I, α1 (COL1A1; Sp1). In the present cohort, higher age and more recently developed treatment protocols were independent risk factors for ON. In children >14.5 years old, TPMT genotype modulated the risk of ON. Additionally, in children <12.9 years old ESR1 genotypes were also implicated in the pathogenesis of ON. Besides greater age and more recent treatment protocols, genetic factors (polymorphisms in ESR1 and TPMT genes) were suggested to be implicated in the pathogenesis of ON and could be potentially used as genetic prognostic markers for ON.

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Section: Discussionmentioning

confidence: 99%

Risk factors for symptomatic osteonecrosis in childhood ALL: A retrospective study of a Slovenian pediatric ALL population between 1970 and 2004

Karas-Kuzelicki¹,

Mencej-Bedrač²,

Jazbec³

et al. 2016

Experimental and Therapeutic Medicine

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“…Metotreksat, pemetreksed, trimeptoprim, primetamin, lamotrigin in sulfasalazin zavirajo delovanje encima DHFR, medtem ko 5-fluorouracil, raltitreksed in pemetreksed zmanjšajo aktivnost encima TS.5,60,61 Poseben primer je 6-merkaptopurin, ko je učinek obraten, saj spremembe v folatnem ciklu vplivajo na metabolno inaktiviranje učinkovine. 62 Prisotnost polimorfizmov v genu MTHFR in zato zmanjšana aktivnost encima lahko vpliva na zdravljenje z analogi purinskih in pirimidinskih baz ali analogi folne kisline, ki delujejo preko kompetitivnega vključevanja v folatni cikel. …”

Section: Metabolne In Hormonske Motnjeunclassified

Spremenjena aktivnost encima 5,10-metilentetrahidrofolat reduktaze (MTHFR) vpliva na razvoj številnih bolezni

et al. 2016

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IzvlečekPomen folatov v fiziologiji je že dolgo znan, prav tako številne patologije, povezane z znižanim folatnim statusom. Pomanjkanje folatov pri posamezniku je lahko posledica nizkega vnosa folata, genetske zasnove posameznika ali sočasnega zdravljenja z zdravili, ki vplivajo na folatni status. Namen tega prispevka je osvetliti pomen ugotavljanja genetskih polimorfizmov, ki pomembno vplivajo na raven biološko aktivne oblike folata. V procesu pretvorbe 5,10-metilen-THF v 5-metil-THF je ključen encim MTHFR, ki je polimorfen, zato pa ima lahko zmanjšano encimsko aktivnost.V slovenski populaciji ima polno aktivnost encima MTHFR le 9,3 % posameznikov, ki so homozigoti za divji tip alelov, medtem ko je povprečna aktivnost encima pri nosilcih mutiranih alelov med 50-60 %. Prisotnost polimorfizma MTHFR predstavlja tveganje za pojav hiperhomocisteinemije in kardiovaskularnih bolezni, nevroloških bolezni, pojav raznih oblik raka, pri nosečnicah pa tudi večje tveganje za pojav okvar ploda. Za ohranjanje ustreznega folatnega statusa so v nekaterih državah uvedli dodajanje folne kisline v prehrano, vendar se je potrebno zavedati, da ta pristop ne bo odpravil pomanjkljivosti v delovanju encima MTHFR, lahko pa ublaži njihov vpliv na končni fenotip posameznika.Prisotnost polimorfizmov v ključnih genih folatnega cikla je pogosta. Zato je ugotavljanje genetske zasnove posameznika smiselno predvsem pri najbolj ranljivih skupinah prebivalstva, npr. pri noseč-nicah in bolnikih, zdravljenih z zdravili, kot so 5-fluorouracil, metotreksat, 6-merkaptopurin, ki se na različne načine vpletajo v presnovno pot folatov. Genotipizacija bi prispevala k identifikaciji bolnikov, pri katerih je povečano tveganje za neustrezen folatni status in zato pomagala pri preprečenju z njim povezanih patoloških stanj. AbstractThe importance of folates in human physiology is well known, as are various pathologies associated with low folate status. Folate deficiency can occur due to low dietary intake, a genetic predisposition or treatment with medicines affecting the folate status. The aim of this paper is to explore the importance of determining genetic polymorphisms, which influence the levels of biologically active folate. MTHFR is involved in the transformation of 5,10-methylene-THF to 5-methyl-THF. Polymorphisms of the MTHRF gene are associated with decreased enzymatic activity.spremenjena aktivnost encima 5,10-metilentetrahidrofolat reduktaze (MthFr) kot dejavnik tveganja za številne bolezni 325 strokoVni čLanek Prispelo: 25. maj 2016Prispelo: 25. maj , sprejeto: 30. jun. 2016 Only 9.3 % of the population in Slovenia display full activity of the MTHFR enzyme; these subjects are non-mutated homozygotes (wild-type alleles). In contrast, the average enzymatic activity in subjects with mutated alleles is between 50 and 60 %. MTHFR polymorphism is associated with an increased risk of hyperhomocysteinemia and cardiovascular diseases, neurological disorders and various types of cancer. There is also an increased risk for congenital malformations. Folic a...

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“…However, it is considerably lower in heterozygotes (53-100%), suggesting that factors other than TPMT genotype may affect enzyme activity [147]. One such factor is SAM, which stabilizes the conformational structure of TPMT by binding into its active site, protecting it from ubiquitylation and degradation [148].…”

Section: Genetic Factors Affecting Thiopurine Metabolismmentioning

confidence: 99%

The Pharmacogenetic Basis of Individual Variation in Thiopurine Metabolism

Blaker

Arenas-Hernandez

Sanderson

2012

Personalized Medicine

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Thiopurines are an important class of immunosuppressive therapy, which have been used in clinical practice for over 50 years. Despite this extensive experience many of the pharmacodynamic and pharmacokinetic properties of these drugs remain unknown. As a consequence there is often no clear explanation for the individual variation in response to treatment, both in terms of efficacy or adverse drug reactions. This review, which emphasizes practice in gastroenterology, summarizes the current understanding of thiopurine drug metabolism and highlights the role of nongenetic and genetic factors other than TPMT, which should be a focus for future research. Correlation of polymorphic variations in these genes with clinical outcomes is expected to clarify the basis for interindividual differences in thiopurine metabolism and enable a more personalized approach to therapy.

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Individualization of Thiopurine Therapy: Thiopurine S -Methyltransferase and Beyond

Cited by 38 publications

References 87 publications

Risk factors for symptomatic osteonecrosis in childhood ALL: A retrospective study of a Slovenian pediatric ALL population between 1970 and 2004

Risk factors for symptomatic osteonecrosis in childhood ALL: A retrospective study of a Slovenian pediatric ALL population between 1970 and 2004

Spremenjena aktivnost encima 5,10-metilentetrahidrofolat reduktaze (MTHFR) vpliva na razvoj številnih bolezni

The Pharmacogenetic Basis of Individual Variation in Thiopurine Metabolism

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