Author/Editor		Bohanec-Grabar, Petra; Dolžan, Vita; Rodriguez-Antona, Cristina
Title		Role of pharmacogenetics for the improvement of cancer tratment
Translated title		Vloga farmakogenetike pri učinkovitejšem zdravljenju raka
Type		članek
Source		Zdrav Vestn
Vol. and No.		Letnik 76, št. Suppl 2
Publication year		2007
Volume		str. II-27-35
Language		eng
Abstract		Background Cancer chemotherapy is associated with a great heterogeneity in patient response that makes the prediction of tumor response and/or drug toxicity very difficult. Many factors such as tumor biology, patient š age, sex and organ function, are known to affect the therapeutic effects of drugs. Although these factors may be considered in decisions on the treatment regimens, the same regimen may result in undertreatment and insufficient therapeutic efficacy in some patients, while it can lead to overtreatmerct and increased toxicity in otherpatients. There is increasing evidence thatgenetic variability in drug metabolizing enzymes and/or drug targets influences drug response and may have a great impact on treatment outcome. This may be especially important,for drugs with a narrow therapetic window and high level of toxicity, such as anticancer drugs. Many studies have shown thatgenetic variation of drug metabolizing enzymes such as cytochromes P450 (CYPs), UDP-glucuronosyltransferase (UGT), glutathione transferases (GSTs), thiopurine methyltransferase (TPMT) or dihydropyrimidine dehydrogenase (DPYD), drug transporters such as p-glycoprotein (MDRI) or reduced folate carrier (RFCZ) and drug targets such as thymidylate synthase (TYMS) or 5,10-methylenetetrcthydrofolate reductase (MTHFR) influence notonly thepharmacokinetics arcd/orpharmacodynamics of anticancer drugs butalso the outcome of cancer treatment. In addition, somatic variations in the cancer cells can also have an impact on the anti-cancerdrug efficacy, such as epidermalgrowthfactorreceptor2protein (HER2) overexpression and epidermalgrowthfactor receptor (EGFR) mutations.
Summary		Izhodišča Izbira načina zdravljenja, pa tudi učinkovitost zdravljenja raka s kemoterapijo se močno razlikuje med bolniki. Medtem, ko je izbira načina zdravljenja odvisna predvsem od bioloških značilnosti in razsežnosti tumorja, pa na učinkovitost zdravljenja vplivajo tudi dejavniki, kot so starost, spol in splošno stanje bolnika, funkcija organa, ki ga zdravimo in podobno. Poleg teh dejavnikov pa na učinkovitost zdravljenja lahko vpliva tudi genetska variabilnost encimov, ki sodelujejo v presnovi ali bioaktivaciji zdravila in molekulskih tarč, na katera zdravila delujejo. Še zlasti so genetski polimorfizmi, ki vplivajo na odziv na zdravila, pomembni za napovedovanja odziva na kemoterapijo, saj je za večino kemoterapevtikov značilna visoka stopnja toksičnosti in ozka terapevtska širina. Številne študije so pokazale, da encimi, ki presnavljajo zdravila, kot na primer citokromi P450 (CYP), UDP-glukuronozil-transferaze (UGT), glutation-transferaze (GST), tiopurin-metiltransferaza (TPMT) ali dihidropirimidin-dehidrogenaza (DPYD), prenašalci zdravil, kot na primer p-glikoprotein (MDR1) ali folatni prenašalec (RFC1) ter tarče zdravil, kot sta na primer timidilat sintaza (TS) ali 5,10-methiletetrahidrofol-reduktaza (MTHFR) vplivajo tako na farmakokinetiko kemoterapevtikov, pa tudi na odziv tumorja in bolnika na zdravljenje. Na odziv nekaterih tumorjev na kemoterapijo pa vplivajo tudi pridobljene somatske mutacije tumorskih celic, kot na primer prekomerna ekspresija receptorja za epidermalni rastni faktor 2 (HER2) in mutacije v genu za epidermalni rastni faktor (EGPR). Zaključki Določanje farmakogenetske variabilnosti dejavnikov, ki vplivajo na presnovo in učinkovitost kemoterapevtikov lahko pomaga pri individualizaciji zdravljenja raka, saj omogoča napovedati odziv posameznika na zdravljenje ter temu ustrezno prilagajanje sheme zdravljenja posameznemu bolniku.
Descriptors		NEOPLASMS POLYMORPHISM (GENETICS) PHARMACOGENETICS CYTOCHROME P-450 TAMOXIFEN THYMIDYLATE SYNTHETASE FLUOROURACIL METHOTREXATE GLUTATHIONE TRANSFERASES