A new mechanism to prevent anthracycline-induced cardiotoxicity while maintaining anticancer activity

Cardiotoxicity is the most serious adverse event associated with anthracyclines which have been widely used in cancer therapy for at least four decades and have led to increased cancer cure rates. A consequence is an increased population with a survival expectancy long enough to carry a lifetime risk for anthracycline-related cardiotoxicity. The potential for cardiovascular problems in many paediatric patients and adults treated with anthracyclines will become apparent in coming years. This cardiotoxicity risk and the requirement for surveillance or intervention increase the cost of health care and compromise quality of life. Since the anthracyclines will continue to be widely used, cardiotoxicity preventative strategies are urgently needed.

Although doxorubicin is primarily considered a TOP2 poison, under certain conditions it can also bind covalently to DNA. This mechanistic switch is controlled by cellular formaldehyde availability. Supplementation of cellular formaldehyde levels using esterase-activated formaldehyde prodrugs switches the mechanism of action of doxorubicin from TOP2 poisoning to covalent DNA adduct formation.

We have observed that the formaldehyde-releasing prodrug AN-7 augments anthracycline anticancer potential while simultaneously reducing cardiotoxicity. We are seeking to identify the mechanism by which formaldehyde-activated anthracyclines protect cardiac cells from undergoing cell death. Although the anthracycline cardiotoxicity problem has been well known for decades, anthracycline covalent lesions have never been examined in the context of this problem.