Anticancer and Cardio-protective Effects of Liposomal Doxorubicin in the Treatment of Breast Cancer
the ONA take:
Doxorubicin (DOX) is a potent chemotherapy drug that has been used successfully in the treatment of several types of cancer, including breast cancer. It is considered one of the most effective chemotherapy agents available and is often used in first- or second-line therapy for localized or metastatic breast cancer, as part of neoadjuvant therapy, or as salvage therapy. However, patients treated with the agent may experience cardiotoxicity.
This classic adverse effect can range from an acute form that develops shortly after exposure to a more severe late form that may result in decreases in left ventricular ejection fraction (LVEF) and subsequent DOX-induced CHF. Due to this effect, DOX use is limited to a cumulative lifetime dose of 550 mg/m2 or 450 mg/m2 in patients who previously received mediastinal radiation.
Doxil (known internationally as Caelyx), a PEGylated liposomal formulation (L-DOX) was developed in an effort to reduce cardiotoxicity of doxorubicin. Although L-DOX has a better cardiovascular safety profile, it is not yet FDA-approved for treating metastatic breast cancer.
Researchers at the Center for Pharmacometrics and Systems Pharmacology at the University of Florida review the mechanism of action of L-DOX, its most common side effects, and the results of studies on its use as a single agent and in combination with other chemotherapeutics.
Breast Cancer: Targets and Therapy
Abstract: Breast cancer (BC) is a highly prevalent disease, accounting for the second highest number of cancer-related mortalities worldwide. The anthracycline doxorubicin (DOX), isolated from Streptomyces peucetius var. caesius, is a potent chemotherapeutic drug that is successfully used to treat various forms of liquid and solid tumors and is currently approved to treat BC. DOX exerts its effects by intercalation into DNA and inhibition of topoisomerases I and II, causing damage to DNA and the formation of reactive oxygen species (ROS), resulting in the activation of caspases, which ultimately leads to apoptosis. Unfortunately, DOX also can cause cardiotoxicity, with patients only allowed a cumulative lifetime dose of 550 mg/m2. Efforts to decrease cardiotoxicity and to increase the blood circulation time of DOX led to the US Food and Drug Administration (FDA) approval of a PEGylated liposomal formulation (L-DOX), Doxil® (known internationally as Caelyx®). Both exhibit better cardiovascular safety profiles; however, they are not currently FDA approved for the treatment of metastatic BC. Here, we provide detailed insights into the mechanism of action of L-DOX and its most common side effects and highlight results of its use in clinical trials for the treatment of BC as single agent and in combination with other commonly used chemotherapeutics.
Keywords: doxil, caelyx, breast cancer, anti-tumor activity, cardiotoxicity
Breast cancer (BC) is the second most frequent cause of cancer-related deaths in women worldwide. It is a heterogeneous disease composed of multiple subtypes with distinct pathological features and clinical implications. Although men are affected, to a lesser degree, the most significant risk factors are gender (women) and older age. Other risk factors include obesity, estrogen exposure, alcohol consumption, and a family history.1 Over the past 2 decades, accumulating evidence, both clinical and experimental, has suggested that BCs with different histopathological and biological features exhibit distinct behaviors that lead to different treatment responses and, therefore, should be given different therapeutic strategies.2 On this basis, at diagnosis, BC patients are systematically tested for the presence of receptors, including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), in order to explore tailored treatment options with molecularly targeted therapies. However, for patients who are triple negative (ER-, PR-, and HER2-), those who have innate or acquired resistance to targeted therapies, and patients whose disease has metastasized, traditional treatment options including surgery, radiotherapy, and chemotherapy are favored.
Anthracycline-based chemotherapy with doxorubicin (DOX) is one of the most efficacious anticancer agents for both early- and late-stage BCs.3 DOX's mechanism of action (Figure 1) on cancer cells begins with its passive diffusion through the phospholipid bilayer membrane of malignant cells into the cytoplasm, where DOX is converted into a semiquinone and generates reactive oxygen species (ROS), causing free radical formation and oxidative stress. In the cytosol, DOX enters the mitochondria causing DNA damage and energetic stress. As a result, the mitochondria release the cytochrome Cprotein, triggering the caspase cascade leading to cell death. From the cytosol, DOX translocates into the nucleus where it intercalates between double-stranded DNA helices and inhibits the enzymes topoisomerases I and II. The resulting damage to DNA leads to free radical generation, alkylation, and activation of the p53 pathway, hence inhibiting cell proliferation and inducing apoptosis. DOX can also hyperactivate the nuclear enzyme poly ADP ribose polymerase (PARP)-1, hence depleting the cell's energy, thereby resulting in autophagy.4–6