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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

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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 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 EC50 of 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.

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Acknowledgments

The authors wish to acknowledge Mary J. Hicks, Mandy R. McKay and Billie McKown for their excellent technical support. This study was supported in part by Gem Pharmaceuticals LLC, Birmingham, AL 35244 and NIH grant R41HL/CA64986. This material is the result of work supported by resources from the Boise VA Medical Center, Boise, ID 83702.

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Authors and Affiliations

  1. Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy and ISU Biomedical Institute, Idaho State University, Meridian, ID, 83209, USA

    Nicole E. Frank & Todd T. Talley

  2. Medicine and Research Services, Department of Veterans Affairs Medical Center, Boise, ID, 83702, USA

    Barry J. Cusack

  3. Division of Gerontology and Geriatric Medicine, School of Medicine, University of Washington, Seattle, WA, 98104, USA

    Barry J. Cusack & Richard D. Olson

  4. Gem Pharmaceuticals, LLC, Birmingham, AL, 35244, USA

    Gerald M. Walsh & Richard D. Olson

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  1. Nicole E. Frank
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  5. Richard D. Olson
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Correspondence to Nicole E. Frank.

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Author’s disclosure of potential conflicts of interest

Nicole E. Frank: None.

Barry J. Cusack: None.

Todd T. Talley: Research funding from Gem Pharmaceuticals, LLC.

Jerry M. Walsh: Consultant for Gem Pharmaceuticals, LLC.

Richard D. Olson: Consultant for Gem Pharmaceuticals, LLC.

Funding/support

The work was sponsored by Gem Pharmaceuticals, LLC Birmingham, AL with funding from NIH grant R41HL/CA64986.

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This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Frank, N.E., Cusack, B.J., Talley, T.T. et al. 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. Invest New Drugs 34, 693–700 (2016). https://doi.org/10.1007/s10637-016-0388-x

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