Anticancer Chemotherapy The relationship between changes in functional cardiac parameters following anthracycline therapy and carbonyl reductase 3 and glutathione S transferase Pi polymorphisms Bilge Volkan-Salanci 1,2 , Hakan Aksoy 3 , Pınar O ¨ zgen Kiratli 1 , Erol Tu ¨lu ¨men 3 , Nilu ¨fer Gu ¨ler 4 , Berna O ¨ ksu ¨zoglu 5 , Lale Tokgo ¨zog ˘lu 3 , Belkıs Erbas ¸ 1 , Mehmet Alikas ¸ifog ˘lu 2 1 Department of Nuclear Medicine, 2 Department of Medical Genetics, 3 Department of Cardiology, 4 Department of Medical Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey, 5 Department of Medical Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital, Ankara, Turkey The aim of this prospective clinical study is to evaluate the relationship between changes in functional cardiac parameters following anthracycline therapy and carbonyl reductase 3 (CBR3p.V244M) and glutathione S transferase Pi (GSTP1p.I105V) polymorphisms. Seventy patients with normal cardiac function and no history of cardiac disease scheduled to undergo anthracycline chemotherapy were included in the study. The patients’ cardiac function was evaluated by gated blood pool scintigraphy and echocardio- graphy before and after chemotherapy, as well as 1 year following therapy. Gene polymorphisms were genotyped in 70 patients using TaqMan probes, validated by DNA sequencing. A deteriorating trend was observed in both systolic and diastolic parameters from GG to AA in CBR3p.V244M polymorphism. Patients with G-allele carriers of GSTP1p.I105V polymorphism were common (60%), with significantly decreased PFR compared to patiens with AA genotype. Variants of CBR3 and GSTP1 enzymes may be associated with changes in short-term functional cardiac parameters. Keywords: CBR3 p.V244M polymorphism, GSTP1 p.I105V polymorphism, Functional cardiac parameters, Anthracycline cardiotoxicity, Cardiac monitoring Introduction Anthracycline cardiotoxicity (AC) is dose-dependent, and prior cardiac disease, age, mediastinal radio- therapy, gender, long-standing hypertension, and complicated diabetes are documented predisposing factors. 1–5 AC is a result of oxidative stress and iron overload, which are generated both by anthracyclines and their metabolites. 6 Clinical follow-up of anthracy- cline-treated patients demonstrates that some patients maintain normal cardiac function even following the highest cumulative doses. On the contrary, some patients develop cardiomyopathy under threshold despite any predisposing factor. 7–9 This may be as a result of imbalance between oxidative stress and detoxifying mechanisms. Some risk factors, such as advanced age, cancer chemotherapeutics, and smoking, decrease the capacity to detoxify oxidative metabolites or increase oxidative stress and contribute to AC. Today, it is believed that AC is a result of both oxidative stress and drug-metabolizing pathways. 6 Beyond extrinsic factors, genetic polymorphisms may account for the variation of the enzymes present in oxidative stress and drug-metabolizing pathways, thus predisposing the individual to AC. 6,10,11 Carbonyl reductases are cytosolic enzymes that reduce anthra- cyclines to cardiotoxic alcohol metabolites (doxorubi- cinol and daunorubicinol) in the human heart. 12 Carbonyl reductase (CBR3) p.V244M polymorphism is positioned in a critical region for interactions with NADP(H) cofactor causing different enzymatic prop- erties between enzyme isoforms, and therefore may play a role in AC. 13 Glutathione S transferases are responsible for the detoxification of free radicals and carcinogens. Glutathione S transferase Pi (GSTP1) p.I105V polymorphism is positioned in the fifth Correspondence to: Bilge Volkan Salanci, Department of Nuclear Medicine, Hacettepe University Faculty of Medicine, Sıhhiye 06100, Ankara, Turkey. Email: bilgev@hacettepe.edu.tr ß 2012 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947812Y.0000000037 Journal of Chemotherapy 2012 VOL. 24 NO.5 285