Cutts - Cellular responses to anticancer drugs
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.
Development of tumour targeted nanoparticles
Anthracycline and anthracenedione anticancer agent primarily induce topoisomerase II poisoning which leads to accumulation of lethal double-strand DNA breaks in cancer cells. The objective is to improve the effectiveness of these widely used anticancer drugs using targeted nanoparticle therapy. Our research addresses the serious side-effects of the anthracycline drugs, also potentially enabling lower doses to be employed. One aspect of this study encapsulates anthracyclines and anthracenediones in the nanoparticles for tumour-specific drug delivery.
We also endeavour to increase the anticancer potency of anthracyclines by developing nanoparticles for localised formaldehyde release in the tumour environment. This requires the development of a carrier system to protect formaldehyde-releasing prodrugs from non-specific esterase-mediated hydrolysis, allowing them to biodistribute intact to tumour tissue. A dramatic tumour growth inhibitory response to our combination treatment in a 'triple negative' MDA-MB-231 breast tumour model indicates that such a treatment strategy could be particularly useful for such tumours in the clinic.
This study requires us to take a multidisciplinary approach in our research which incorporates expertise in a range of diverse areas including drug-DNA interactions, cell biology, nanotechnology, biomolecular surface analysis, medicinal chemistry and preclinical drug evaluation.