Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products: 

  • Topoisomerase Inhibitors Type II: Epirubicin (Ellence)

    • • Pharmacology of Epirubicin in Cancer Treatment

        (Gemini AI Assisted) [May 6, 2025]

        Introduction Epirubicin is an anthracycline antibiotic and a stereoisomer of doxorubicin, specifically the 4'-epimer [1]. This structural difference, involving the orientation of the hydroxyl group on the daunosamine sugar moiety, leads to modifications in its pharmacological profile, particularly concerning its metabolism and toxicity, while largely retaining the anticancer activity of doxorubicin [1, 2]. Epirubicin is widely used in the treatment of various solid tumors and hematological malignancies. Mechanism of Action The mechanisms by which epirubicin exerts its cytotoxic effects are similar to those of other anthracyclines, notably doxorubicin: DNA Intercalation: Epirubicin intercalates between DNA base pairs, distorting the DNA helix structure [2]. This physical binding interferes with DNA replication and transcription, hindering the synthesis of nucleic acids and proteins, which are essential for cell division and survival [3] Topoisomerase II Inhibition: Like doxorubicin, epirubicin inhibits the enzyme topoisomerase II. Epirubicin stabilizes the covalent complex formed between topoisomerase II and DNA (the "cleavable complex"), which prevents the re-ligation of DNA double-strand breaks created by the enzyme during DNA replication and transcription [3, 4]. The accumulation of these unrepaired double-strand breaks triggers cell cycle arrest and apoptosis. Generation of Reactive Oxygen Species (ROS): Epirubicin can undergo redox cycling, leading to the formation of semiquinone free radicals and subsequent generation of ROS, such as superoxide anions and hydroxyl radicals [2]. These ROS can cause oxidative damage to DNA, proteins, and cellular membranes, contributing to its cytotoxicity. This mechanism is also thought to play a role in anthracycline-induced cardiotoxicity [5]. Some studies suggest that epirubicin may be taken up by cells more rapidly and achieve higher intracellular concentrations than doxorubicin, potentially influencing its activity [1]. Pharmacokinetics (ADME) Absorption: Epirubicin is not orally bioavailable and is administered intravenously [6]. Distribution: After IV administration, epirubicin is rapidly and widely distributed into body tissues, with a large volume of distribution. Epirubicin binds extensively to plasma proteins. Similar to doxorubicin, its penetration into the central nervous system (CNS) is poor [6, 7]. Metabolism: Epirubicin is extensively metabolized in the liver  [7]. The main metabolic pathways include reduction to epirubicinol (which has some cytotoxic activity), cleavage of the daunosamine sugar to form aglycones, and conjugation (glucuronidation and sulfation) [1, 7]. Epirubicin appears to be more rapidly and extensively metabolized than doxorubicin, which may contribute to its faster clearance and potentially different toxicity profile [1]. [12] Metabolism: Epirubicin is extensively metabolized in the liver and also in other tissues by cytoplasmic aldo-keto reductases [7, 13]. The main metabolic pathways include reduction to epirubicinol (which has some cytotoxic activity), cleavage of the daunosamine sugar to form aglycones, and conjugation (glucuronidation and sulfation) [1, 7]. Epirubicin appears to be more rapidly and extensively metabolized than doxorubicin, which may contribute to its faster clearance and potentially different toxicity profile [1,12]. Clinical Applications Epirubicin is used in the treatment of a range of cancers, often as part of combination chemotherapy regimens. Its approved indications can vary by region but may include: By far primary clinical use:  Breast cancer (both in adjuvant and metastatic settings) [8] Gastric and esophageal cancer [8] Ovarian [14] Lung cancer (small cell)  [11] Epirubicin is sometimes preferred over doxorubicin in certain regimens due to perceptions of a more favorable toxicity profile, particularly regarding cardiotoxicity at equi-effective doses. Adverse Effects and Toxicities The adverse effect profile of epirubicin is qualitatively similar to that of doxorubicin, but there are quantitative differences, especially concerning cardiotoxicity. Cardiotoxicity: Cardiotoxicity remains a significant dose-limiting toxicity. Like doxorubicin, epirubicin can cause both acute (e.g., arrhythmias, transient ECG changes) and chronic, cumulative dose-dependent cardiomyopathy leading to congestive heart failure [5, 9]. However, clinical data generally suggest that epirubicin is less cardiotoxic than doxorubicin on an equimolar or equieffective dose basis. The maximum recommended cumulative lifetime dose for epirubicin is typically higher (e.g., around 900 mg/m²) than that for doxorubicin (450-550 mg/m²) before the risk of cardiotoxicity becomes substantial [5, 9]. Cardiac function monitoring is essential during treatment. Myelosuppression:  Bone marrow suppression, particularly neutropenia, is the most common acute dose-limiting toxicity [8]. Thrombocytopenia and anemia also occur. The nadir is usually seen 10-14 days post-administration. Nausea and Vomiting: Epirubicin is moderately to highly emetogenic, often requiring prophylactic antiemetics [8]. Alopecia: Hair loss is common and often complete [8]. Mucositis/Stomatitis: Inflammation and ulceration of the oral mucosa can occur. Extravasation: Epirubicin is a vesicant, and extravasation during IV infusion can cause severe local tissue injury and necrosis [6]. Secondary Malignancies: There is an increased risk of developing secondary cancers, such as acute myeloid leukemia, following treatment with epirubicin [8]. Red Discoloration of Urine: Patients should be advised that their urine may turn red for 1-2 days after administration due to the drug's color; this is a harmless effect [6]. Mechanisms of Resistance Resistance to epirubicin is a significant clinical challenge and shares mechanisms with doxorubicin resistance: Increased Drug Efflux: Overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (MDR1) and Multidrug Resistance-associated Protein 1 (MRP1), actively pumps epirubicin out of cancer cells, reducing its intracellular concentration and efficacy [10]. Alterations in Topoisomerase II: Decreased expression or mutations in the topoisomerase II enzyme can reduce its sensitivity to epirubicin [10]. Enhanced Detoxification: Increased activity of detoxifying enzymes, like glutathione S-transferases, can metabolize epirubicin or scavenge the ROS it produces [10]. Defects in Apoptotic Pathways: Alterations in cellular pathways that control programmed cell death can render cells resistant to epirubicin-induced damage [10]. Conclusion Epirubicin is an important anthracycline chemotherapeutic agent with a spectrum of activity and mechanisms of action similar to doxorubicin. An important distinguishing feature is its potentially more favorable cardiotoxicity profile, which may allow for higher cumulative doses and an improved therapeutic index in some clinical settings. Nevertheless, it still carries significant risks of myelosuppression and other toxicities common to anthracyclines. Careful patient selection, dose management, and monitoring are essential for its safe and effective use in cancer treatment. References 1.  Plosker, G. L., & Faulds, D. (1993). Epirubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in cancer. Drugs, 45(5), 788–856. https://link.springer.com/article/10.2165/00003495-199345050-00011. 2.  Shandilya M Sharma S Das P Charak S Molecular-Level Understanding of the Anticancer Action Mechanism of Anthracyclines Advances in Precision Medicine Oncology (H Arouk H and Hassan B, eds) 27 October 2020 https://www.intechopen.com/chapters/73668. 3.  Tewey, K. M., Rowe, T. C., Yang, L., Halligan, B. D., & Liu, L. F. (1984). Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science, 226(4673), 466–468. https://pubmed.ncbi.nlm.nih.gov/6093249/ . 4.  Marinello J Delcuratolo M Capranico Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives Int J Mol Sci 2018, 19(11), 3480 https://www.mdpi.com/1422-0067/19/11/3480 5. Van Dalen, E. C., Michiels, E. M., Caron, H. N., & Kremer, L. C. (2010). Different anthracycline derivates for reducing cardiotoxicity in children with cancer. Cochrane Database of Systematic Reviews, (5), CD005006. 6.  Robert, J. (1993). Clinical pharmacokinetics of epirubicin. Clinical Pharmacokinetics, 24(4), 275–287. https://pubmed.ncbi.nlm.nih.gov/8070217/ 7. Camaggi C Strocchi E Comparsi R Testoni F Angelelli B Pannuti F   Biliary excretion and pharmacokinetics of 4'epidoxorubicin (epirubicin) in advanced cancer patients. https://pubmed.ncbi.nlm.nih.gov/3463434/ 8. Epirubicin https://en.wikipedia.org/wiki/Epirubicin 9. Ryberg M Nielsen D et al. Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. Journal of Clinical Oncology 16(11) November 1, 1998. https://ascopubs.org/doi/10.1200/JCO.1998.16.11.3502 10. Bukowski K Kciuk M Kontek Mechanisms of  Multidrug Resistance in Cancer Chemotherapy Int J Mol Sci 2020, 21(9), 3233 https://www.mdpi.com/1422-0067/21/9/3233 11.  Rosenthal M Kefford R Raghavan D Stuart-Harris R Epirubicin: a phase II study in recurrent small-cell lung cancer https://pubmed.ncbi.nlm.nih.gov/1713130/ 12.  Epirbicin:  Package Insert / Prescribing Info (Drugs.com)  https://www.drugs.com/pro/epirubicin.html 13.  Heibein A Sprowl AJ MacLean DA Parissenti Abstract 3546: Role of the “1C” Aldo-Keto Reductases in Resistance to Doxorubicin in MCF-7 breast cancer cells Cancer Res (2010) 70 (8_Supplement): 3546 https://aacrjournals.org/cancerres/article/70/8_Supplement/3546/564127/Abstract-3546-Role-of-the-1C-Aldo-Keto-Reductases 14.  Havsteen H Bertelsen K et al. A phase 2 study with epirubicin as second-line treatment of patients with advanced epithelial ovarian cancer Gynecol Oncol 1996 Nov; 63(2):  210-215. https://pubmed.ncbi.nlm.nih.gov/8910629/

    • Overview:

      • Epirubicin (Ellence)

       

      • Epirubicin is an isomer of doxorubicin characterized by increased lipophilicity.⁷ 

      • Epirubicin belongs to the anthracycline class of anticancer drugs, inhibiting DNA and RNA synthesis following intercalation between DNA pairs.⁹ 

        • Intercalation between base pairs induces DNA cleavage (mediated by topoisomerase II) and as a consequence cell death.

        • Epirubicin exhibits antineoplastic effects at any stage of the cell cycle.

        • This agent is approved as adjuvant treatment for breast cancer in those patients exhibiting axillary node involvement.⁹

          • Although first approved in this adjuvant setting (early-stage, node -positive breast cancer), epirubicin is also employed in both metastatic breast cancer therapy and gastroesophageal cancer.³

           

          • Epirubicin and Cyclophosphamide before Doxcetaxel in Early Breast Cancer¹¹

            Attribution: Ejlertsen B Epirubicin and cyclophosphamide before doxcetaxel in early breast cancer.  https://www.youtube.com/watch?v=QlzwQTwQvIs (1/2017) ecancer Youtube Channel:  https://www.youtube.com/channel/UCGb_Xmf5mzvyXC7NOjsonkg

           

          • Should Anthracyclines Be Given in Advanced Gastroesophageal Cancer?¹²

            Attribution: Bendell J Chau I Janjigian Y Shah M Should Anthracyclines Be Given in Advanced Gastroesophageal Cancer.https://www.youtube.com/watch?v=tCqeV6xbs-k (11/2016) OncLiveTV Yourtube Channel:  https://www.youtube.com/channel/UC3aRpa3CR_w4JrxYv_r_pDg

    • Absorption, Distribution, Biotransformation, Excretion:

      • Epirubicin is administered by the intravenous (IV) route of administration.⁹ 

      • The drug exhibits a volume of distribution (Vd) of about 24 L/kg with protein binding of about 80% (albumin).

      • Epirubicin undergoes substantial hepatic and extrahepatic metabolism.⁹  

      • As noted by the volume of distribution, epirubicin is substantially distributed in tissue.¹⁰ 

      • Drug elimination is mainly biliary (<15% of epirubicin is found in the urine).¹⁰ 

        • Epirubicin metabolism involves conversion to metabolites that are either mainly or completely inactive.

        • Some of these metabolites include a 13-dihydro derivative, epirubicinol, 2 glucuronides and 4 aglycones.

        • Epirubicin glucuronides and epirubicinol metabolites describe a unique metabolic pathway in humans which may account for improved drug tolerance when compared with doxorubicin.

          • A 3-compartment model describes epirubicin pharmacokinetics.

          • The median half-life associated with these compartments (phases) are about 3 minutes, 1 hour and 32 hours.¹⁰

    • Toxicity: 

      • Epirubicin toxicity is the same as that described earlier for doxorubicin.⁷

        • Doxorubicin Toxicities

          Acute toxicities associated with doxorubicin administration include: Myelosuppression Alopecia Mucositis G.I. disturbances (nausea/vomiting). The acute, dose-limiting toxicity is myelosuppression. Antiemetic drugs are administered along with doxorubicin. Antiemetic drugs that may be helpful in managing acute emesis associated with chemotherapeutic agents, such as doxorubicin, which are classified as having a high "emetic risk." (Navari RM Management of Nausea and Vomiting June 1, 2015;(https://www.cancernetwork.com/cancer-management/management-nausea-and-vomiting) Antiemetic Agents:   Chemotherapy-Induced Emesis13 Granisetron (Sustol, Sancuso) Ondansetron (Zofran, Zuplenz) Palonosetron (Aloxi) Dexamethosone (Ozurdex et al) Metochlopramide (Reglan)  Haloperidol (Haldol) Dronabinol (Syndros, Marinol) Nabilone (Cesamet) Prochlorperazine (Compro) Lorazepam (Atavan) Natupitant (Akyneo [natupitant + palonosetron]) Aprepitant/Fosaprepitant. Pro-drug  (Emend) Extended infusion time reduces both nausea and likelihood of cardiotoxicity. As noted above, doxorubicin is a significant vesicant and following extravasation significant skin necrosis may occur. Accordingly, infusions through a central venous catheter is likely appropriate. Acute and Chronic Toxicities:8 Anthracycline Cardiotoxicity14 Attribution: Russell, III, R Antracycline Cardiotoxicity:  The Role of Cardio-Oncology in Management https://www.youtube.com/watch?v=cpfeGjTCT20 (9/2012; published 3/2018) Yale Cancer Center Youtube Channel:  https://www.youtube.com/channel/UClDVKSccJn3qHFnmkCxgHPQ Cardiotoxicity is both an acute and chronic associated with doxorubicin administration. Cardiac toxicity may occur even though the drug remains effective in tumor treatment. Cardiotoxicity may occur associated with anthracycline-based anticancer agents given alone or in combination with other chemotherapy. Furthermore, cardiotoxicity is also associated with the monoclonal anticancer antibody, trastuzumab (Herceptin). The combination of anthracycline and trastuzumab, in patients with tumors expressing high HER2/neu levels, is contraindicated due to enhancement of anthracycline -related cardiac damage by trastuzumab.  Use of doxorubicin in treating children is particularly problematic given increased pediatric patients sensitivity to cardiotoxic effects.8 Acute cardiotoxicity due to doxorubicin clinically presents usually as arrhythmias which may include heart block. Most serious presentations are described by a pericarditis-myocarditis syndrome characterized by: Fever Pericarditis and CHF (congestive heart failure). This serious,acute side effect may be fatal and could occur even with low, cumulative doxorubicin doses.  Chronic cardiotoxicity occurs due to cumulative myocardial damage.8  Myocyte pathology involves both myofiber disruption and cytoplasmic reticulum dilation. In latter stages, a "diffuse myocardial fibrosis" may be observed. This pathology is likely unique to anthracycline anticancer agents allowing for differential diagnosis (versus ischemic myocardial damage or viral cardiomyopathy). Anthracycline-caused cardiotoxicity often presents with typical CHF symptoms such as: Cough Weight gain Peripheral edema and in some more severe cases, Pulmonary edema(severe cases). Risk factors for anthracycline-caused cardiotoxicity include: Female gender Concurrent or previous chest radiation Cardiac comorbidity Age. CHF associated with doxorubicin administration is often treatable using usual CHF therapies, such as diuresis.8 Secondary Leukemia:7,8 Another late-onset doxorubicin (as well as other anthracyclines) toxicity is secondary leukemia. The side effect is likely due to balanced chromosomal translocations due to topoisomerase II "poisoning." The risk level of secondary acute myeloid leukemia (AML) is about 2% or less. In those clinical settings in which the likelihood of cure is high, the risk of a secondary leukemia is and especially important consideration, such as in the pediatric setting or in anthracycline drug administration as adjuvant treatment for breast cancer.7,8

    • Clinical Uses:

      • Although first approved in this adjuvant setting (early-stage, node -positive breast cancer), epirubicin is also employed in both metastatic breast cancer therapy and gastroesophageal cancer.³