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Effects of MnDPDP andICRF-187 on Doxorubicin-Induced Cardiotoxicityand Anticancer Activity1
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. (medicin)
GE Healthcare, Oslo, Norway. (medicin)
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. (medicin)
Audacter Consulting, Helensburgh, Scotland. (medicin)
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2012 (English)In: Translational Oncology, ISSN 1936-5233, Vol. 5, no 4, 252-259 p.Article in journal (Refereed) Published
Abstract [en]

Oxidative stress participates in doxorubicin (Dx)–induced cardiotoxicity. The metal complex MnDPDP and its metaboliteMnPLED possess SOD-mimetic activity, DPDP and PLED have, in addition, high affinity for iron. Mice wereinjected intravenously with MnDPDP, DPDP, or dexrazoxane (ICRF-187). Thirty minutes later, mice were killed, theleft atria were hung in organ baths and electrically stimulated, saline or Dx was added, and the contractility wasmeasured for 60 minutes. In parallel experiments, 10 μM MnDPDP or MnPLED was added directly into the organbath. The effect of MnDPDP on antitumor activity of Dx against two human tumor xenografts (MX-1 and A2780)was investigated. The in vitro cytotoxic activity was studied by co-incubating A2780 cells with MnDPDP, DPDP,and/or Dx. Dx caused a marked reduction in contractile force. In vivo treatment with MnDPDP and ICRF-187 attenuatedthe negative effect of Dx. When added directly into the bath, MnDPDP did not protect, whereas MnPLEDattenuated the Dx effect by approximately 50%. MnDPDP or ICRF-187 did not interfere negatively with the antitumoractivity of Dx, either in vivo or in vitro. Micromolar concentrations of DPDP but not MnDPDP displayed anin vitro cytotoxic activity against A2780 cells. The present results show that MnDPDP, after being metabolized toMnPLED, protects against acute Dx cardiotoxicity. Both in vivo and in vitro experiments show that cardioprotectiontakes place without interfering negatively with the anticancer activity of Dx. Furthermore, the results suggest thatthe previously described cytotoxic in vivo activity of MnDPDP is an inherent property of DPDP.

Translational Oncology (2012) 5, 252–259

Place, publisher, year, edition, pages
2012. Vol. 5, no 4, 252-259 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-80755DOI: 10.1593/tlo.11304ISI: 000311488600005OAI: diva2:548129

funding agencies|Medical Research Council of Southeast Sweden|FORSS-85191|PledPharma AB||

Available from: 2012-08-29 Created: 2012-08-29 Last updated: 2014-10-28

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Kurz, TinoAndersson, RolfKarlsson, Jan Olof G.
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