Doxorubicin (DOX) is a powerful, well-established and highly efficacious drug in many kinds of cancers like solid tumors, leukemia, soft tissue sarcoma, breast cancer, small cell carcinoma of the lung and esophageal carcinomas. Despite its broad effectiveness, DOX therapy is associated with specific toxicities to cardiac tissues. DOX-induced cardiotoxicity can persist for years with no clinical symptoms. However, its prognosis becomes poor after the development of overt heart failure, possibly even worse than ischemic or idiopathic dilated cardiomyopathies. Due to the successful action of DOX as chemotherapeutic agent, several strategies have been tried to prevent or attenuate its side effects. DOX-induced cardiotoxicity occurs due to the formation of free reactive oxygen radicals, direct DNA damage and/or interference with DNA repair, induction of immune reactions and activation of apoptotic pathway. Although DOX-induced injury appears to be multifactorial, a common denominator among most of the proposed mechanisms is cellular damage mediated by reactive oxygen species (ROS).
Carvedilol, a third-generation, nonselective β-adrenoreceptor antagonist that also possesses α1-adrenergic blocking property. A number of experimental studies have demonstrated that carvedilol possesses both ROS scavenging and ROS suppressive effects.
Metoprolol is a β1-selective adrenergic receptor blocking agent. When carvedilol and metoprolol were recently compared in clinical trials for heart failure, each showed beneficial β-blocker effects such as improved symptoms, quality of life, exercise tolerance, and ejection fraction in echocardiography, with no differences between both groups.
The present study was performed on 40 adult male albino rats, which divided as follow:
(1) Group I (Control group):
Rats were injected with saline intraperitoneally (I.P).
(2) Group II (DOX group):
Doxorubicin hydrochloride was injected intraperitoneally once weekly for 6weeks in a dose of 2mg/kg per week [A total cumulative dose of (12 mg/kg)].
(3) Group III (DOX+CRV group):
Rats were given doxorubicin hydrochloride (2mg/kg/week I.P) and
oral daily dose of carvedilol (30 mg/kg) by gastric tube for 6 weeks.
(4) Group IV (DOX+MET group):
Rats were given doxorubicin hydrochloride (2mg/kg/week I.P) and oral daily dose of metoprolol (60 mg/kg) by gastric tube for 6 weeks.
After 24 hours from the last doxorubicin injection, the rats of all groups
were sacrificed. Heart specimens were taken and fixed in 10% formalin, processed and embedded in paraffin. Sections of 5um were prepared to be stained by Haematoxylin and Eosin, Masson's trichrome stain and Immunohistochemical staining for caspase3.
Cardiotoxicity occurred in all DOX-injected rats. DOX produced massive change in the myocardium mainly in the form of increased cytoplasmic eosinophilia, degeneration of myocardial tissue, vacuolization of the cardiomyocytes, myofibrillar disorganization and loss, mononuclear cellular infiltration and nuclear changes in the form of pyknosis, karyorhexis and karyolysis .Apoptotic cells were also noticed.
In DOX group cardiac tissue sections stained with Masson's trichrome stain showed increase in collagen content (interstitial fibrosis)as compared to the control group.
In the current work, the cardiac tissue sections from DOX group revealed distinct positive immunoreactivity for caspace 3 indicating that apotosis is a main contributor mechanism in Dox- induced cardiotoxicity.
Masson’s trichrome staining demonstrated that the collagen area (interstitial fibrosis) was significantly lower in both carvidelol treated group and metoprolol treated group when compared with DOX group. statistical analysis revealed that carvidelol was superior to metoprolol.
Immunohistochemical results demonstrated that both carvidelol and metoprolol attenuated apoptosis when compared with DOX group. Statistical analysis revealed that carvidelol was superior to metoprolol.
In conclusion accumulative dose of doxorubicin (12 mg/ kg) administered over a period of 6 weeks, produced a well evident cardiotoxic injury. Both carvidelol and metoprolol have beneficial effect in DOX-induced cardiotoxicity, statistical analysis revealed that carvidelol was superior to metoprolol while the difference between both groups was statistically insignificant. We speculate that the beneficial effect of both drugs cannot be explained only by antioxidant effect but also by the beta blockade effect of both drugs. This speculation needs further studies.
Recommendation:
• Long term studies for evaluation of the role of carvidelol and metoprolol in DOX-cardiotoxicity is recommended.
• Larger numbers of experimental animals should be used.
• Ultrastructural studies should be done.
• Pharmacological studies for evaluation of the role of β1 blockade in DOX-cardiotoxicity should be performed.
|
