Epirubicin is an anthracycline drug used for chemotherapy. It can be used in combination with other medications to treat breast cancer in patients who have had surgery to remove the tumor. It is marketed by Pfizer under the trade name Ellence in the US and Pharmorubicin or Epirubicin Ebewe elsewhere.
Similarly to other anthracyclines, epirubicin acts by intercalating DNA strands. Intercalation results in complex formation which inhibits DNA and RNA synthesis. It also triggers DNA cleavage by topoisomerase II, resulting in mechanisms that lead to cell death. Binding to cell membranes and plasma proteins may be involved in the compound's cytotoxic effects. Epirubicin also generates free radicals that cause cell and DNA damage.
Epirubicin is favoured over doxorubicin, the most popular anthracycline, in some chemotherapy regimens as it appears to cause fewer side-effects. Epirubicin has a different spatial orientation of the hydroxyl group at the 4' carbon of the sugar - it has the opposite chirality - which may account for its faster elimination and reduced toxicity. Epirubicin is primarily used against breast and ovarian cancer, gastric cancer, lung cancer and lymphomas.
Medical uses
Adjuvant therapy
The aim of Epirubicin as adjuvanted therapy is to eradicate micro metastasis and prolong disease free survival.[1][2]
Vs standard adjuvant therapy
The Standard adjuvant therapy is a combination of cyclophosphamide, methotrexate and fluorouracil (CMF). In comparison to this the Epirubicin therapy contains fluorouracil/epirubicin/cyclophosphamide (FEC). Three large randomized studies have directly compared the epirubicin-containing regimen fluorouracil/epirubicin/cyclophosphamide (FEC) with CMF in the adjuvant setting. Trial one and two contained premenopausal node-positive women with breast cancer, Trial three pre- and postmenopausal women with node-positive or negative breast cancer. It was discovered that FEC is at least as effective as CMF in premenopausal women with node positive- or negative breast cancer and that FEC produced no additional benefit in terms of 5-year relapse-free or overall survival.[1]
Pharmacology
Mechanism of action
The mechanism of action of epirubicin is similar to that of doxorubicin and other anthracycline drugs. The observed clinical differences between epirubicin and doxorubicin can be explained by the pharmacokinetic differences based on the different affinity to DNA and lipophilicity, as there is no indication that different mechanisms are involved in their activity.[4]
Epirubicin first forms a complex with DNA by intercalation of its planar rings between nucleotide base pairs. (Pharmacia & Upjohn Company LLC, 1999) This inhibits replication and transcription and triggers DNA cleavage by topoisomerase II. Epirubicin then stabilizes the topoisomerase II-DNA complex, resulting in irreversible DNA strand breakage, leading to cell death.[5] Epirubicin is also capable of generating cytotoxic free radicals, which are very reactive against DNA, cell membranes and mitochondria.[4][6]
Side effects
The most common side effects of the Epirubicin are alopecia, nausea/vomiting, cardiotoxicity, leukopenia, and stomatitis.[13] Cardiotoxicity is a severe side effect and the exact pathway is still unknown. However, there is good evidence to suggest that cardiotoxicity is caused at least in part by the avid interaction of anthracyclines with iron, resulting in the formation of metal ion complexes.[1] It was first observed in adult cancer patients as clinical congestive heart failure (CHF), characterized by pulmonary oedema, fluid overload, and effort intolerance, was initially reported in 1979 by Von Hoff et al.[14] at 2.2% overall with a cumulative doxorubicin dose-dependent incidence of CHF of 3%, 7%, and 18% at 400, 550, and 700 mg/m2, respectively.[15]
There are a lot of adverse effects of epirubicin related with the dose-limiting. The major commun negative effects are fever, diarrhea, nausea and vomiting.[7]
Chemistry
Epirubicin is a 4'-epi-isomer of doxorubicin and a derivative of daunorubicin. As an anthracycline antibiotic it belongs to several chemical classes such as: aminoglycosides, tetracene quinones, p-quinones, primary alpha-hydroxy ketone and tertiary alpha-hydroxy ketones. Due to numerous ionisable groups, it has multiple pKa (pKa1 = 9.17 (phenol); pKa2 = 9.93 (amine); pKa3 = 12.67 (hydroxyl)) and is soluble in a variety of solvents (DMSO 125 mg/mL; Ethanol 120 mg/mL; In water, 93 mg/L at 25 °C (est)). It has a melting point of 344.53 and a boiling point of 810.3±65.0 °C at 760 mmHg.[17]
Its shelf life (def. as the time it takes to degrade 10% from the initial concentration) has been documented as at least 14 and 180 days at 25 °C and 4 °C, respectively in a 0.9% sodium chloride solution in polypropylene syringes.[18]
Synthesis
There are multiple ways of synthesizing epirubicin depending on which starting material is used as a precursor.
Daunorubicin
Development history
The first trial of epirubicin in humans was published in 1980.[21] Upjohn applied for approval by the U.S. Food and Drug Administration (FDA) in node-positive breast cancer in 1984, but was turned down because of lack of data. In 1999 Pharmacia (who had by then merged with Upjohn) received FDA approval for the use of epirubicin as a component of adjuvant therapy in node-positive patients.
Patent protection for epirubicin expired in August 2007.
References
- Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741 Journal of Clinical Oncology, April 2003^
- Adjuvant chemotherapy for early breast cancer: optimal use of epirubicin The Oncologist, 2005^
- Epirubicin: a review of its efficacy as adjuvant therapy and in the treatment of metastatic disease in breast cancer Drugs & Aging, November 1999^