Cardioprotective effects of zofenopril, a new angiotensin-converting enzyme inhibitor, on doxorubicin-induced cardiotoxicity in the rat

Abstract

We have studied the effect of zofenopril, a new angiotensin-converting enzyme inhibitor in preventing cardiac injury induced by chronic doxorubicin treatment in rats. Cardiac function was assessed by measuring changes in electrocardiogram (ECG) tracings, haemodynamics and cardiac responses in vivo to isoprenaline, 4 weeks after suspension of doxorubicin treatment, in vehicle-treated rats and in animals receiving zofenopril (15 mg/kg/os/day) alone, doxorubicin (1.5 mg/kg i.v. once a week for 5 weeks) or zofenopril+doxorubicin treatment. Doxorubicin induced a significant lengthening of the QαT interval, which was completely prevented by zofenopril treatment. The cardiac positive inotropic effect induced by i.v. isoprenaline was selectively depressed by doxorubicin (no changes in chronotropic responses) and this adverse effect of doxorubicin was also prevented in zofenopril+doxorubicin pretreated rats. Doxorubicin induced a significant increase in relative heart weight, which was likewise prevented in zofenopril+doxorubicin treated rats. In separate experiments, zofenopril did not interfere with the antitumor activity of doxorubicin (inhibition of tumor growth in nude mice xenografted with A2780 human tumor line). In conclusion, the oral administration of zofenopril is able to significantly ameliorate, up to 4 weeks after the end of doxorubicin administration, doxorubicin-induced cardiotoxicity without affecting the antitumor activity of this anthracycline.

Introduction

Anthracyclines such as doxorubicin and epirubicin are among the most widely used cytotoxic drugs for the treatment of a wide spectrum of human tumors Arcamone, 1981, Hitchcock-Bryan et al., 1986, Fischer et al., 1989, Mouridsen et al., 1990, Bonadonna, 1984: their use in cancer chemotherapy is limited by the occurrence of a severe dose-related cardiomyopathy Rhoden et al., 1993, Buzdar et al., 1985, Von Hoff et al., 1979, Dardir et al., 1989, Torti et al., 1986, eventually leading to congestive heart failure. Anthracycline-induced congestive heart failure almost invariably develops in patients receiving cumulative doses of doxorubicin over 550 mg/m² or epirubicin over 1000 mg/m²: these patients also become unresponsive to positive inotropic agents within 2–3 months from the start of treatment Singal and Natasha, 1998, Lefrak et al., 1973.

The efficacy of anthracyclines as cytotoxic against several types of human tumors has prompted intensive efforts in the searching of drug treatments (such as antioxidants and metal chelators), which may reduce or prevent the risk of developing cardiotoxicity and congestive heart failure. However, the cardioprotection afforded by these treatments has not been demonstrated consistently effective DeSilvestro et al., 1996, Unverferth et al., 1985, Van Vleet et al., 1980. In particular, the difficulty of achieving constant plasma concentrations of antioxidant drugs and their poor uptake at heart level are the major limiting factors of this approach Myers et al., 1983, Dorr, 1996, Wang and Kang, 1999, Konorev et al., 1999.

A few studies have also suggested that angiotensin-converting enzyme inhibitors, which are widely used for treatment of a number of cardiovascular diseases (hypertension, congestive heart failure, acute myocardium infarction and diabetic nephropathy) may exert a protective role toward anthracycline-induced cardiotoxicity.

Jensen et al. (1996) reported, in a limited number of patients with advanced breast cancer, that two angiotensin-converting enzyme inhibitors, enalapril and ramipril, ameliorate symptoms of anthracycline-induced congestive heart failure. A few studies about the use of angiotensin-converting enzyme inhibitors treatment to prevent experimental anthracycline-induced cardiotoxicity Tokudome et al., 2000, Maeda et al., 1997, Al-Shabannah et al., 1998 are available. Two of these studies were either performed in vitro (Maeda et al. 1997), or after single administration of doxorubicin and an angiotensin-converting enzyme inhibitor in vivo (Al-Shabanah et al., 1998). Moreover, none of these studies addressed whether the concomitant administration of an angiotensin-converting enzyme inhibitor may have a detrimental effect on the antitumor efficacy of doxorubicin.

Zofenopril is a new angiotensin-converting enzyme inhibitor characterized by a remarkable uptake by cardiac tissue, producing a striking and long-lasting inhibition of cardiac angiotensin-converting enzyme as compared to other drugs of this class Sun and Mendelsohn, 1991, Subissi et al., 1999. Moreover, owing to the presence of a sulphydryl group, it is also an effective radical scavenger with antioxidant properties Chopra et al., 1992, Mak et al., 1990, Napoli et al., 1999. Zofenopril has shown to exert a remarkable cardioprotective effect in a number of in vitro and in vivo models of ischaemic myocardial injury Ferrari et al., 1992, Subissi et al., 1999 and its early administration in patients with myocardial infarction improve their long-term survival (Ambrosioni et al., 1995).

The aim of this study was to assess whether pretreatment with zofenopril can prevent the development of anthracycline-induced cardiotoxicity and heart failure in rats.

With this aim, rats were treated with zofenopril, given orally in the diet, at a nominal dose (15 mg/kg/day) producing a full antihypertensive effect in this species Mitchell et al., 1996, DeForrest et al., 1989, Cushman et al., 1989, Gonzales et al., 2000. The effect of this dose regimen on doxorubicin-induced cardiopathy was assessed up to 4 weeks from the end of doxorubicin administration.

In addition, to check whether zofenopril treatment determines any interference with the antitumoral activity of doxorubicin, we assessed the efficacy of doxorubicin treatment in nude mice xenografted with the human ovarian carcinoma cell line A2780 and simultaneously receiving zofenopril by oral gavage.