The effect of monohydroxyethylrutoside on doxorubicin-induced cardiotoxicity in patients treated for metastatic cancer in a phase II study

Abstract

The purpose of this study was to investigate the cardioprotective effect of the semisynthetic flavonoid 7-monohydroxyethylrutoside (monoHER) on doxorubicin (DOX)-induced cardiotoxicity in a phase II study in patients with metastatic cancer. Eight patients with metastatic cancer were treated with DOX preceded by a 10 min i.v. infusion of 1500 mg m À2 monoHER. Five patients were examined by endomyocardial biopsy after reaching a cumulative dose of 300 mg m À2 . Histopathological changes in the cardiomyocytes (Billingham score) were compared with those described in literature for patients treated with DOX only. The mean biopsy score of the patients was higher (2.7) than the mean score (1.4) of historical data of patients who received similar cumulative doses of DOX. Although there is a considerable variability in few investigated patients, it was indicative that monoHER enhanced DOX-induced cardiotoxicity. However, the antitumour activity of DOX seemed better than expected: three of the four patients with metastatic soft-tissue sarcoma had a partial remission and the fourth patient stable disease. It is likely that the relatively high dose of monoHER is responsible for the lack of cardioprotection and for the high response rate in patients with soft-tissue sarcoma possibly by depleting the glutathione defense system in both heart and tumour.

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

“…Data from clinical trials have also yielded negative results regarding the cardioprotective potential of several antioxidants, namely vitamin E (158), N-acetylcysteine (54,193), or mono-HER (28). Although these agents have been so far tested in rather small clinical trials with numerous imperfections, accumulating body of evidence argues against the value of these agents as clinically effective cardioprotectants in ANT cardiotoxicity settings.…”

Inhibition of Polymorphic Human Carbonyl Reductase 1 (CBR1) by the Cardioprotectant Flavonoid 7-monohydroxyethyl Rutoside (monoHER)

“…Fig. 1) showed a favorable cardioprotective profile in several models of anthracycline-related cardiotoxicity, and is now being tested in phase II clinical trials (9)(10)(11). Recent data suggest that the overall cardioprotective profile of monoHER results from the combination of various activities including chelation of intracellular iron, and scavenging of free radicals (12)(13)(14)(15).…”

A novel application of maleimide for advanced drug delivery: in vitro and in vivo evaluation of maleimide-modified pH-sensitive liposomes

“…DOX, a potent anticancer drug, has a limited clinical application due to its severe side effects, such as myelosuppression, cardiotoxicity, and gastrointestinal toxicity. 23,24 We utilized the liposomes as a carrier of DOX to protect the drug from rapid metabolism and reduce its side effects by enhancing selectivity for tumor tissues. For the preparation of DOX-encapsulating liposomes, a liposome suspension ([lipid] = 3 mg/mL, 1 mL) and a DOX solution (300 µg/mL, 1 mL) were pre-heated at 60°C for 15 minutes and then mixed at 60°C for a further 15 minutes.…”