DOXORUBICIN AND CPEC INDUCED CARDIOXICITY: association with the GTPase gene Rac2, and drug transporter genes MRP1 and MRP2

Chemotherapy with anthracyclines is associated with cardiotoxicity. Besides known risk factors such as cumulative dose and mediastinal irradiation, there are indications that genetic variation might also be associated with the development of anthracycline induced cardiotoxicity. In the current study a retrospective case control analysis was performed in oncology patients having received anthracyclines. Allele frequencies of genetic polymorphisms in several candidate genes between patients with and without anthracycline-induced cardiotoxicity and between cases and healthy control subjects were studied. Anthracycline-induced cardiotoxicity was associated with the T7508A variant in the GTPase Rac2, a gene with a known functionality in NAD(P)H oxidase activity. Furthermore, we tested in vitro in a rat cardiomyocyte cell line (H9c2), whether the anthracycline doxorubicine and the cytotoxic and cardiotoxic drug cyclopentenyl cytosine (CPEC) influenced the expression of the candidate genes (p22phox, Rac2, MRP1 and MRP2), that were reported earlier to be related with doxorubicin-induced cardiotoxicity. CPEC caused a small decrease in the expression of MRP2 and did not influence the expression of the other genes. The expression of MRP1 was decreased after incubation with doxorubicin whereas no changes were found in the expression of Rac2, p22phox and MRP2. It is concluded that although the expression of Rac2 did not seem to be influenced by doxorubicin, a SNP in the GTPase Rac2 was associated with anthracycline induced cardiotoxicity. As demonstrated by their influence on MRP1 and MRP2 respectively, doxorubicin and CPEC decreased the expression of genes involved in multi drug resistance.