title: Comparative effects of doxorubicin and a doxorubicin analog, 13-deoxy, 5-iminodoxorubicin (GPX-150), on human topoisomerase IIβ activity and cardiac function in a chronic rabbit model.
abstract: 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 IIβ/DNA reaction, we also compared potency of DOX and DIDOX to inhibit topoisomerase IIβ 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 IIβ 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 IIβ with an EC50of 40.1 μM while DIDOX did not have any apparent effect on topoisomerase IIβ at the concentrations used in the study (0.1-100 μM). Conclusions Unlike DOX, DIDOX did not cause chronic cardiotoxicity and did not appear to interact with topoisomerase IIβ in decatenation assays consistent with the hypothesis that inhibition of the topoisomerase IIβ/DNA reaction may be a contributor of the mechanism of chronic DOX cardiotoxicity.
authors: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy and ISU Biomedical Institute, Idaho State University, Meridian, ID, 83209, USA. frannic2@pharmacy.isu.edu.
authors: Nicole E
authors: NE
authors: Frank
authors: Medicine and Research Services, Department of Veterans Affairs Medical Center, Boise, ID, 83702, USA.|Division of Gerontology and Geriatric Medicine, School of Medicine, University of Washington, Seattle, WA, 98104, USA.
authors: Barry J
authors: BJ
authors: Cusack
authors: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy and ISU Biomedical Institute, Idaho State University, Meridian, ID, 83209, USA.
authors: Todd T
authors: TT
authors: Talley
authors: Gem Pharmaceuticals, LLC, Birmingham, AL, 35244, USA.
authors: Gerald M
authors: GM
authors: Walsh
authors: Division of Gerontology and Geriatric Medicine, School of Medicine, University of Washington, Seattle, WA, 98104, USA.|Gem Pharmaceuticals, LLC, Birmingham, AL, 35244, USA.
authors: Richard D
authors: RD
authors: Olson
mesh_terms: D000818:Animals; D016279:Atrial Function, Left / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D011817:Rabbits; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D059005:Topoisomerase II Inhibitors; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; C000604876:5-imino-13-deoxydoxorubicin
keywords: Cardiotoxicity; Doxorubicin; Rabbit; Topoisomerase II