Individualizacija terapije tamoksifenom i polimorfizam CYP2D6

master's thesis

• Title (english): Individualization of tamoxifen therapy and CYP2D6 polymorphism
• Author: Edita Bešić
• Mentor: Jelena Osmanović (mentor)
• Committee member: Marija Bakula (član povjerenstva)
• Committee member: Ante Tvrdeić (predsjednik povjerenstva)
• Committee member: Jelena Osmanović (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; Zagreb
• Defense date and country: 2024-07-12, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Clinical Pharmacology and Toxicology

Abstract

Tamoksifen je hormonska terapija koja se koristi u liječenju i prevenciji karcinoma dojke ovisnih o estrogenu. Karcinomi dojke ovisni o estrogenu maligni su tumori koji na svojim stanicama eksprimiraju receptore za estrogen. Tamoksifen je selektivni modulator estrogenski receptora, koji na tkivo dojke ima antiestrogeni učinak, te time sprječava proliferacijski učinak estrogena na stanice i posljedično rast tumora. Da bi se postigao terapijski učinak, tamoksifen se u organizmu metabolizira uglavnom putem CYP2D6 enzima do svojeg temeljnog aktivnog metabolita, endoksifena. Gen koji kodira za enzim CYP2D6 je vrlo polimorfan, podložan varijabilnostima, što uzrokuje fenotipski raznoliku enzimatsku aktivnost. Definirana su četiri metabolička fenotipa CYP2D6: vrlo brzi, normalni, intermedijarni i spori metabolizatori. To utječe na učinkovitost lijekova koji se metaboliziraju putem CYP2D6. Razvojem personalizirane medicine i individualnog pristupa liječenju, razvijene su smjernice za odabir i doziranje nekih lijekova prema genetičkom profilu pojedinca. Tako vrlo brzi i normalni metabolizatori tamoksifena postižu terapijski učinak primjenom standardnih doza. Nasuprot tome, spori i intermedijarni metabolizatori imaju nižu koncentraciju endoksifena u plazmi, što smanjuje terapijski učinak tamoksifena i povećava rizik povrata bolesti pa im se preporuča alternativna terapija.

Abstract (english)

Tamoxifen is a hormone therapy used in the treatment and prevention of hormone-dependent breast cancers. Estrogen dependent breast cancers are malignant tumors that express receptors for the estrogen. Tamoxifen acts as selective estrogen modulators with antiestrogen effect on breast tissue, which prevents the proliferative effect of estrogen on cells and consequently the growth of tumors. In order to achieve a therapeutic effect, tamoxifen in the body must first be metabolized mainly by the CYP2D6 enzyme to its main active metabolite, endoxifen. The gene that codes for the CYP2D6 enzyme is highly polymorphic, prone to variability, which causes phenotypically diverse enzymatic activity. By translating the genotype into the phenotype, four CYP2D6 phenotypes were defined: very fast, normal, intermediate and slow metabolizers. This affects the effectiveness of drugs that are metabolized by CYP2D6. With the development of personalized medicine and an individual approach to treatment, guidelines were developed for the selection and dosage of some drugs according to the individual's genetic profile. Thus, very fast and normal metabolizers of tamoxifen achieve a therapeutic effect using standard doses. In contrast, slow and intermediate metabolizers have a lower concentration of endoxifen in plasma, which reduces the therapeutic effect of tamoxifen and increases the risk of disease relapse, so alternative therapy is recommended for them.

• Keywords: tamoksifen; hormonski ovisan karcinom dojke; CYP2D6; polimorfizam gena
• Keywords (english): tamoxifen; hormon-dependent breast cancer; CYP2D6; polymorphism of gene
• Language: croatian
• URN:NBN: urn:nbn:hr:105:774225
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-07-02 08:57:16