Anthracyclines (or anthracycline antibiotics) are a class of drugs (CCNS or cell-cycle non-specific) used in cancer chemotherapy derived from Streptomyces bacterium Streptomyces peucetius var. caesius.
The anthracyclines are among the most effective anticancer treatments ever developed and are effective against more types of cancer than any other class of chemotherapeutic agents. Their main adverse effect is cardiotoxicity, which considerably limits their usefulness. Use of anthracyclines has also been shown to be significantly associated with cycle 1 severe or febrile neutropenia. Other adverse effects include vomiting.
The first anthracycline discovered was daunorubicin (trade name Daunomycin), which is produced naturally by Streptomyces peucetius, a species of actinobacteria. Doxorubicin (trade name Adriamycin) was developed shortly after, and many other related compounds have followed, although few are in clinical use.
Anthracyclines are used to treat various cancers and as of 2012 were among the most commonly used chemotherapeutic agents. Doxorubicin and its derivative, epirubicin, are used in breast cancer, childhood solid tumors, soft tissue sarcomas, and aggressive lymphomas. Daunorubicin is used to treat acute lymphoblastic or myeloblastic leukemias, and its derivative, idarubicin is used in multiple myeloma, non-Hodgkin's lymphomas, and breast cancer. Other anthracycline derivates include nemorubicin, used for treatment of hepatocellular carcinoma, pixantrone, used as a second-line treatment of non-Hodgkin's lymphomas, sabarubicin, used for non-small cell lung cancer, hormone refractory metastatic prostate cancer, and platinum- or taxane-resistant ovarian cancer, and valrubicin, which is used for the topical treatment of bladder cancer.
Mechanism of action
Anthracyclines have four mechanisms of action:
- Inhibition of DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly growing cancer cells.
- Inhibition of topoisomerase II enzyme, preventing the relaxing of supercoiled DNA and thus blocking DNA transcription and replication. Some sources say that topoisomerase II inhibitors prevent topoisomerase II turning over which is needed for dissociation of topoisomerase II from its nucleic acid substrate. In other words, topoisomerase II inhibitors stabilise the topoisomerase II complex after it has broken the DNA chain. This leads to topoisomerase II mediated DNA-cleavage, producing DNA breaks.
- Iron-mediated generation of free oxygen radicals that damage the DNA, proteins and cell membranes.
- Induction of histone eviction from chromatin that deregulates DNA damage response, epigenome and transcriptome.
Anthracyclines can cause cardiotoxicity. This cardiotoxicity may be caused by many factors, which may include inhibition and/or poisoning of topoisomerase-IIB in cardiomyocytes, interference with the ryanodine receptors of the sarcoplasmic reticulum, free radical formation in the heart, or from buildup of metabolic products of the anthracycline in the heart. The cardiotoxicity often presents as ECG changes (especially change in the frequency of QRS complex) and arrhythmias, or as a cardiomyopathy leading to heart failure (sometimes presenting many years after treatment). This cardiotoxicity is related to a patient's cumulative lifetime dose. A patient's lifetime dose is calculated during treatment, and anthracycline treatment is usually stopped (or at least re-evaluated by the oncologist) upon reaching the maximum cumulative dose of the particular anthracycline.
There exists evidence that the effect of cardiotoxicity increases in long-term survivors, from 2% after 2 years to 5% after 15 years.
In addition to staying below the cumulative doses, various prevention measures may be employed by the oncologist in order to reduce the risk of cardiotoxicity. Cardiac monitoring are recommended at 3, 6, and 9 months. Other measures include the use of Dexrazoxane, the use of liposomal preparations of doxorubicin when appropriate, as well as the administration of doxorubicin over longer infusion rates:
- Dexrazoxane is a cardioprotectant that is sometimes used to reduce the risk of cardiotoxicity; it has been found to reduce the risk of anthracycline cardiotoxicity by about two-thirds, without affecting response to chemotherapy or overall survival.[needs update]
- The liposomal formulations of daunorubicin and doxorubicin are less toxic to cardiac tissue than the non-liposomal form because a lower proportion of drug administered in the liposome form is delivered to the heart.
- Longer infusion rates will result in a reduced plasma level and a much lower left ventricular peak concentration.
At least one study which found lower verbal memory performance on tests of immediate and delayed recall suggests that anthracycline may increase the risk for developing "chemobrain".
Daunorubicin was first isolated from streptomyces early in the 1960s by groups in Italy (at Farmitalia) and France (at Rhone-Poulenc), each of which published in 1963. Doxorubicin was discovered after a strain of Streptomyces was mutated to produce different compounds.
Effort soon began to develop derivatives with better activity and less cardiotoxicity. Most of these derivatives were made by tweaking compounds produced by bacteria, or by modifying the bacteria themselves. Amrubicin was the first derivative created by de novo synthesis and was first published in 1989 by scientists from Sumitomo.
- Trevor A, Katzung B, Masters S. Pharmacology: Examination and Board Review. Chapter 54, "Anthracycilne Antibiotics." Accessed through www.accesspharmacy.com on 1/25/13.
- Fujiwara, A.; Hoshino, T.; Westley, J. W. (1985). "Anthracycline Antibiotics". Critical Reviews in Biotechnology 3 (2): 133. doi:10.3109/07388558509150782.
- Weiss RB (December 1992). "The anthracyclines: will we ever find a better doxorubicin?". Semin. Oncol. 19 (6): 670–86. PMID 1462166.
- Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (June 2004). "Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity". Pharmacol. Rev. 56 (2): 185–229. doi:10.1124/pr.56.2.6. PMID 15169927.
- Peng X, Chen B, Lim CC, Sawyer DB (June 2005). "The cardiotoxicology of anthracycline chemotherapeutics: translating molecular mechanism into preventative medicine". Mol. Interv. 5 (3): 163–71. doi:10.1124/mi.5.3.6. PMID 15994456.
- Lyman GH, Kuderer NM, Crawford J, et al. Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy. Cancer.2011;117(9):1917-1927.
- Hanada M. Amrubicin, Chapter 6 in Case Studies in Modern Drug Discovery and Development. Eds. Huang X and Aslanian RG. John Wiley & Sons, 2012 ISBN 9780470601815 P 104
- MInotti G et al. Anthracyclines in Encyclopedia of Molecular Pharmacology, 2nd Edition, Volume 1. Eds. Offermanns S and Rosenthal W. Springer, 2008. ISBN 9783540389163 P 91ff
- Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
- Pang B, Qiao X, Janssen L, Velds A, Groothuis T, Kerkhoven R, Nieuwland M, Ovaa H, Rottenberg S, van Tellingen O, Janssen J, Huijgens P, Zwart W, Neefjes J (2013). "Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin". Nature Communications 4: 1908. doi:10.1038/ncomms2921. PMID 23715267.
- Zhang, S.; Liu, X.; Bawa-Khalfe, T.; Lu, LS.; Lyu, YL.; Liu, LF.; Yeh, ET. (2012). "Identification of the molecular basis of doxorubicin-induced cardiotoxicity.". Nature Medicine 18 (11): 1639–42. doi:10.1038/nm.2919. PMID 23104132.
- Minotti, G.; Menna, P.; Salvatorelli, E.; Cairo, G.; Gianni, L. (2004). "Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity". Pharmacological Reviews 56 (2): 185–229. doi:10.1124/pr.56.2.6. PMID 15169927.
- Kremer L, van Dalen E, Offringa M, Ottenkamp J, Voûte P (2001). "Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study". J Clin Oncol 19 (1): 191–6. PMID 11134212.
- van Dalen EC, Caron HN, Dickinson HO, Kremer LC (2008). Van Dalen EC, ed. "Cardioprotective interventions for cancer patients receiving anthracyclines". Cochrane Database Syst Rev (2): CD003917. doi:10.1002/14651858.CD003917.pub3. PMID 18425895.
- Forssen, E. A.; Tökes, Z. A. (1979). "In vitro and in vivo studies with adriamycin liposomes". Biochemical and Biophysical Research Communications 91 (4): 1295–1301. doi:10.1016/0006-291X(79)91207-5. PMID 526304.
- Kesler SR, Blayney DW. Neurotoxic Effects of Anthracycline- vs Nonanthracycline-Based Chemotherapy on Cognition in Breast Cancer Survivors. JAMA Oncol. 2016 Feb 1;2(2):185-92. doi: 10.1001/jamaoncol.2015.4333.PMID 26633037
- Weiss RB (December 1992). "The anthracyclines: will we ever find a better doxorubicin?". Seminars in Oncology 19 (6): 670–86. PMID 1462166.
- Suarato A, Angelucci F, Geroni C. Ring-B modified anthracyclines. Curr Pharm Des. 1999 Mar;5(3):217-27. Review. PMID 10066891
- Grein A, et al. Descrizione e classificazione di un attinomicete (Streptonryces peucetius sp. nova) produttore di una sostanza ad attivita antitumorale. Giorn. Microbiol. 11: 109~ 118, 1963
- Dubost M. et al. A New Antibiotic with Cytostatic Properties: Rubidomycin. C R Hebd Seances Acad Sci. 1963 Sep 9;257:1813-5. French. PMID 14090569
- Arcamone F, Cassinelli G, Fantini G, et al. (1969). "Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius". Biotechnol Bioeng 11 (6): 1101–10. doi:10.1002/bit.260110607. PMID 5365804.
- Hanada M. Amrubicin, Chapter 6 in Case Studies in Modern Drug Discovery and Development. Eds. Huang X and Aslanian RG. John Wiley & Sons, 2012 ISBN 9780470601815 P 106
- Media related to Anthracyclines at Wikimedia Commons