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Frederine, a new and promising protector against doxorubicin-induced cardiotoxicity.
Clin Cancer Res 2001; 7(5):1378-84CC

Abstract

The flavonoid 7-monohydroxyethylrutoside (monoHER) can protect against doxorubicin-induced cardiotoxicity. A drawback of monoHER therapy would be the relatively high dose needed to obtain complete protection (500 mg/kg in mice). Therefore, we synthesized a series of new compounds with improved antioxidant properties. After characterization of antioxidant activity, cardioprotection in vitro, and possible toxic properties in hepatocytes, we selected Frederine for additional investigations in vivo. In the present study, it was found that this compound did not induce weight loss or (gross) organ changes in mice in a treatment schedule of 170 mg/kg i.p., 5 times/week during 2 weeks. We recorded the electrocardiogram telemetrically in mice during and 2 weeks after the combined treatment with doxorubicin (4 mg/kg, i.v.) and 5 times Frederine (68 mg/kg, i.p.; equimolar to 100 mg/kg monoHER) for 6 weeks. Complete protection against doxorubicin-induced cardiotoxicity was found, indicating that Frederine is at least 5 times more potent than monoHER. Frederine did not have a negative influence on the antiproliferative effects of doxorubicin on A2780, OVCAR-3, and MCF-7 cells in vitro and on OVCAR-3 xenografts grown in nude mice when administered 5 min before doxorubicin (8 mg/kg i.v.) and 4 days thereafter with an interval of 24 h. It can be concluded that we succeeded in designing a better cardioprotector than monoHER. Therefore, Frederine merits further investigation as a possible protector against doxorubicin-induced cardiotoxicity in cancer patients.

Authors+Show Affiliations

Department of Medical Oncology, University Hospital Vrije Universiteit, 1081 HV Amsterdam, The Netherlands. f.vanacker@azvu.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11350909

Citation

van Acker, F A., et al. "Frederine, a New and Promising Protector Against Doxorubicin-induced Cardiotoxicity." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 7, no. 5, 2001, pp. 1378-84.
van Acker FA, Boven E, Kramer K, et al. Frederine, a new and promising protector against doxorubicin-induced cardiotoxicity. Clin Cancer Res. 2001;7(5):1378-84.
van Acker, F. A., Boven, E., Kramer, K., Haenen, G. R., Bast, A., & van der Vijgh, W. J. (2001). Frederine, a new and promising protector against doxorubicin-induced cardiotoxicity. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 7(5), pp. 1378-84.
van Acker FA, et al. Frederine, a New and Promising Protector Against Doxorubicin-induced Cardiotoxicity. Clin Cancer Res. 2001;7(5):1378-84. PubMed PMID: 11350909.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Frederine, a new and promising protector against doxorubicin-induced cardiotoxicity. AU - van Acker,F A, AU - Boven,E, AU - Kramer,K, AU - Haenen,G R, AU - Bast,A, AU - van der Vijgh,W J, PY - 2001/5/15/pubmed PY - 2001/7/20/medline PY - 2001/5/15/entrez SP - 1378 EP - 84 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 7 IS - 5 N2 - The flavonoid 7-monohydroxyethylrutoside (monoHER) can protect against doxorubicin-induced cardiotoxicity. A drawback of monoHER therapy would be the relatively high dose needed to obtain complete protection (500 mg/kg in mice). Therefore, we synthesized a series of new compounds with improved antioxidant properties. After characterization of antioxidant activity, cardioprotection in vitro, and possible toxic properties in hepatocytes, we selected Frederine for additional investigations in vivo. In the present study, it was found that this compound did not induce weight loss or (gross) organ changes in mice in a treatment schedule of 170 mg/kg i.p., 5 times/week during 2 weeks. We recorded the electrocardiogram telemetrically in mice during and 2 weeks after the combined treatment with doxorubicin (4 mg/kg, i.v.) and 5 times Frederine (68 mg/kg, i.p.; equimolar to 100 mg/kg monoHER) for 6 weeks. Complete protection against doxorubicin-induced cardiotoxicity was found, indicating that Frederine is at least 5 times more potent than monoHER. Frederine did not have a negative influence on the antiproliferative effects of doxorubicin on A2780, OVCAR-3, and MCF-7 cells in vitro and on OVCAR-3 xenografts grown in nude mice when administered 5 min before doxorubicin (8 mg/kg i.v.) and 4 days thereafter with an interval of 24 h. It can be concluded that we succeeded in designing a better cardioprotector than monoHER. Therefore, Frederine merits further investigation as a possible protector against doxorubicin-induced cardiotoxicity in cancer patients. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/11350909/Frederine_a_new_and_promising_protector_against_doxorubicin_induced_cardiotoxicity_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11350909 DB - PRIME DP - Unbound Medicine ER -