Comparative effects of doxorubicin and a doxorubicin analog, 13-deoxy, 5-iminodoxorubicin (GPX-150), on human topoisomerase II[beta] activity and cardiac function in a chronic rabbit model

Summary Purpose A novel doxorubicin (DOX) analog, 13-deoxy, 5-iminodoxorubicin (DIDOX), was synthesized to prevent quinone redox cycling and alcohol metabolite formation, two prevailing hypotheses of anthracycline cardiotoxicity. The chronic cardiotoxicity of DOX and DIDOX was compared. Since a recent hypothesis posits that DOX-induced chronic cardiotoxicity may be mediated by inhibition of the topoisomerase II[beta]/DNA reaction, we also compared potency of DOX and DIDOX to inhibit topoisomerase II[beta] decatenation of kinetoplast DNA (kDNA) (a series or interlocking small rings of DNA). Methods We compared DIDOX with DOX to alter cardiac function in a chronic rabbit model. We also compared potency to inhibit decatenation of kDNA by purified topoisomerase II[beta] in vitro. Results DOX and DIDOX caused similar decreases in white and red blood cell counts indicating similar positions on the dose-response curve for cytotoxic efficacy. However, DOX but not DIDOX elicited a decrease in left ventricular fractional shortening and contractility of isolated left atrial preparations obtained at sacrifice. Histological scoring of apex and left ventricular free wall samples showed that DOX-treated rabbits had significantly more cardiac injury than samples from DIDOX or saline-treated rabbits. DOX inhibited decatenation of DNA by topoisomerase II[beta] with an EC50 of 40.1 [mu]M while DIDOX did not have any apparent effect on topoisomerase II[beta] at the concentrations used in the study (0.1-100 [mu]M). Conclusions Unlike DOX, DIDOX did not cause chronic cardiotoxicity and did not appear to interact with topoisomerase II[beta] in decatenation assays consistent with the hypothesis that inhibition of the topoisomerase II[beta]/DNA reaction may be a contributor of the mechanism of chronic DOX cardiotoxicity.