VIENNA, Austria—Anthracyclines are antibiotics that are also one of the most potent classes of chemotherapeutic agents. As noted in a 2007 paper published in the International Journal of Nanomedicine, titled “Anthracycline-incued cardiotoxicity and the cardiac-sparing effect of liposomal formulation,” “They are highly effective against a broad spectrum of malignancies, including lymphoma, gastric cancer, small cell lung cancer, sarcoma and breast cancer.” The issue with these drugs is that they are also known to cause heart damage; the paper goes on to note that anthracyclines have “a well-recognized cumulative-dose related cardiotoxic profile that limits the extent to which they can be used safely. In clinical practice, most clinicians limit the cumulative dose of doxorubicin (the most widely used agent in this group) to 400-450 mg/m2, but considerable cardiac damage is now known to occur at cumulative dosages considerably below this level.”
A study presented at the EuroEcho-Imaging 2014 meeting by Prof. Jutta Bergler-Klein and Prof. Mariann Gyöngyösi of the Medical University of Vienna, however, has demonstrated a new technique that wraps these drugs in a fatty cover, known as a liposome, can reduce heart damage. EuroEcho-Imaging is the annual meeting of the European Association of Cardiovascular Imaging, a branch of the European Society of Cardiology.
“Cardiotoxicity can occur acutely or up to 30 years after chemotherapy and is the second most common cause of death in cancer patients, after secondary malignancy in childhood cancer survivors,” said Bergler-Klein. “Risk increases with more chemotherapy or when radiation is also given. That is why it’s so important to use a regimen that has as few cardiac side effects as possible.”
In this study, “Cardiotoxic effects of different anthracyclines compared to liposomal doxorubicin in an experimental study with echocardiography and magnetic resonance imaging” the team worked with two dozen pigs, which were randomized to receive the human dose-equivalent of conventional doxorubicin, Myocet (a liposome-encapsulated doxorubicin-citrare complex) or epirubicin in three cycles. The pigs' cardiac function was assessed by echocardiography and magnetic resonance imaging (MRI) both at baseline and a follow-up after roughly three months. Laboratory follow-up included hematology, renal function and measurement of cardiac enzymes troponin and BNP (with the epirubicin group excluded from final analyses due to low survival levels).
The analysis showed that the group that received Myocet presented with better diastolic and systolic function in the left and right ventricles compared to conventional doxorubicin, as well as presenting with less fibrosis development in the myocardium, as shown by MRI and histology staining.
The analysis showed that the group that received Myocet presented with better diastolic and systolic function in the left and right ventricles compared to conventional doxorubicin. The Myocet group also presented with less fibrosis development in the myocardium, as shown by MRI and histology staining: after treatment, myocardial fibrosis was found in 60 percent of animals treated with doxorubicin, compared to 33 percent in animals that received Myocet.
Bergler-Klein noted that the fact that heart damage was seen even in the Myocet group, “despite the fact that the pigs were young, healthy and received anthracyclines for only a short period,” emphasizes the need for patients on anthracyclines “to receive cardiac monitoring using echocardiography and biomarkers, and MRI where indicated.”
“Anthracyclines are a cornerstone of oncology treatment, but the more cycles needed to fight cancer, the more cardiotoxic side effects the patient will have,” said Bergler-Klein. “We have shown that the cardiotoxicity can be reduced with liposomal encapsulation. Cardiac monitoring of all patients receiving anthracyclines is essential to detect early deterioration of the heart and give preventive treatment.”
“Many patients who recover after chemotherapy have asymptomatic heart damage which can become symptomatic as they get older. When heart problems are picked up early patients can be given preventive treatment including ACE inhibitors, angiotensin receptor blockers or beta blockers to prevent the progression to overt heart failure,” she added.
As for the reason behind this approach's effectiveness, the study's abstract notes that “liposome encapsulation limits the cytostatic delivery to healthy tissues,” with Bergler-Klein noting that “More of the drug reaches the cancer cells because there is less degradation, and there are fewer side effects on healthy cells because the fat cover acts as a barrier. The drug stays in the bloodstream longer, allowing higher cumulative doses to be given.”
Expounding on that, Toxipedia reports that one theory for the decreased damage, discussed in the 2003 paper “Current Status of Liposomal Anthracycline Therapy in Metastatic Breast Cancer,” is that it is due to “the greater permeability of the microvasculature promoted by cancerous cells. So, the lipid-encapsulated drug is simply taken up in greater quantities by cancer cells because they produce 'leakier' blood vessels. But the lipid capsule also slows the rate at which the drug binds to the proteins of healthy cells, and may deliver the chemotherapy over a longer period of time, potentially enhancing its effectiveness in comparison to standard formulations.”
The team is conducting gene expression profiling on the study's histology samples to investigate the better outcome and cardiac function seen in the Myocet group, and so far have found differences in the expression of the genes that control energy use and the metabolic state, with the Myocet group showing better regulation.