Pharmacogenetics of Anthracyclines

Abstract

Anthracyclines constitute a fundamental part of the chemotherapy regimens utilized to treat a number of different malignancies both in pediatric and adult patients. These drugs are one of the most efficacious anticancer agents ever invented. On the other hand, anthracyclines are cardiotoxic. Childhood cancer survivors treated with anthracyclines often undergo cardiac complications which are influenced by genetic variations of the patients. The scientific literature comprises numerous investigations in the subject of the pharmacogenetics of anthracyclines. In this review, we provide a comprehensive overview of this research topic. Genetic variants are proposed targets in the personalized treatment in order to individualize dosing and therefore reduce side effects.

Is there scope for better individualisation of anthracycline cancer chemotherapy?

“…Some of the intersubject variation in anthracycline pharmacokinetics and metabolism could be due to genetic variations in the expression and activity of transporters and enzymes. The effects of polymorphisms in genes coding for enzymes and transporters involved in anthracycline pharmacokinetics and pharmacodynamics has been the subject of several reviews 82–87 . With respect to pharmacokinetics, anthracycline clearance is not dependent on 1 primary elimination pathway, but involves a number of hepatic metabolic enzymes and transporters.…”

“…The effects of polymorphisms in genes coding for enzymes and transporters involved in anthracycline pharmacokinetics and pharmacodynamics has been the subject of several reviews. [82][83][84][85][86][87] 91 However, the clinical recommendations primarily extend to more intensive monitoring on the basis of added genetic risk. 91 In recognition of its multifactorial nature, 3 groups have developed combined clinical and genetic models to predict risk of anthracycline cardiotoxicity in adults and children [93][94][95] using a case-control candidate gene approach.…”

Új és hagyományos irányok a gyermekkori akut lymphoblastos leukaemia biológiájában és ellátásában

“…A toxicitás megelőzésére több citosztatikumnak új, biztonságosabb formája is lé-tezik (főként pegilált vagy liposzomális kivitel) [26], illetve segítséget nyújt a vérplazma gyógyszerszintjének rutinszerű monitorozása (hazánkban évek óta figyelt paraméter a metotrexátkoncentráció, de bevezetés alatt áll az aszparaginázaktivitás mérése is). Korábbi saját farmakogenetikai vizsgálataink eredményei csatlakoznak ahhoz a nemzetközi irányvonalhoz, hogy bizonyos génva-riánsok előzetes meghatározása (kemoterapeutikumokkal kölcsönható metabolizáló enzimek, transzporterek és hisztokompatibilitásért felelős antigének polimorf locusainak genotipizálása) előrevetítheti a nem kívánt mel- ABL1 = Abelson murine leukemia viral oncogene homolog 1; ALL = akut lymphoblastos leukaemia; AML1 = akut myeloid leukaemia-1 protein; BCR = breakpoint cluster region; CD = differenciációs klaszter; CDKN = cyclin dependent kinase inhibitor; cIg/sIg = citoszolikus/sejtfelszíni immunglobulin; DNMT = DNS-metiltranszferáz; ETV6 = ets variant gene 6 (TEL oncogene); FLT3 = fms related tyrosine kinase 3; IDH = isocitrate dehydrogenase; IGH = immunoglobulin heavy locus; IL3 = interleukin-3 (colony-stimulating factor, multiple); KRAS = Kirsten rat sarcoma viral oncogene homolog; MLL = mixed-lineage leukemia; NOTCH = Notch (Drosophila)-homológ; NRAS = neuroblastoma; PBX1 = pre-B-cell leukemia homeobox 1; Ph-like = Philadelphia-transzlokáció-szerű; RAS = viral (v-ras) oncogene homolog; RUNX1 = Runt-related transcription factor 1; TCF3 = transcription factor 3; TCR = T-sejt-receptor; TdT = terminális dezoxinukleotid-transzferáz lékhatásokra való hajlamot [30][31][32]. Sokat fejlődött továbbá a kiegészítő (szupportív) terápia, amelynek hála az akut adverz reakciók jól kezelhetővé váltak.…”

Draft Genome Sequence of Micromonospora sp. Strain WMMA1996, a Marine Sponge-Associated Bacterium

“…Members of the genus Micromonospora are important producers of antibiotics, having yielded more than 700 compounds of medical value over the years ( 1 ). Compounds such as the aminoglycoside antibiotics gentamicin ( 2 , 3 ) and netilmicin ( 2 ), the antitumor antibiotics lomaiviticins ( 4 – 7 ) and tetrocarcins ( 8 , 9 ), the anthracycline antibiotics ( 10 – 12 ), and the enediyne calicheamicin ( 13 – 15 ) highlight both the structural diversity and medicinal impact of Micromonospora -derived natural products. In addition to compounds with clear antimicrobial or anticancer activities, members of the Micromonospora have produced natural products such as juvenimicin C ( 16 ), an activator of phase II detoxifying enzymes with cancer chemopreventive activities, and diazepinomicin, a farnesylated dibenzodiazepine with antioxidant and antiproteolytic activities proposed to protect against an assortment of age-related diseases such as diabetes, atherosclerosis, and various cancers ( 17 ).…”