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Daunorubicin, the prototypical anthracycline

Doxorubicin

Epirubicin

Idarubicin

Anthracyclines (or anthracycline antibiotics) are a class of drugs (CCNS or cell-cycle non-specific)^[1] used in cancer chemotherapy derived from Streptomyces bacterium Streptomyces peucetius var. caesius.^[2]

These compounds are used to treat many cancers, including leukemias, lymphomas, breast, uterine, ovarian, and lung cancers.

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.^{[citation needed]}^[3]^[4]^[5] 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.^[6] 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.^[3]

Examples[edit]

Available agents include:

Daunorubicin (Daunomycin)
Daunorubicin (liposomal)
Doxorubicin (Adriamycin)
Doxorubicin (liposomal)
Epirubicin
Idarubicin
Valrubicin, used only to treat bladder cancer
Mitoxantrone, anthracycline analog

Mechanism of action[edit]

Anthracycline has four mechanisms of action:

Inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells.^[7]
Inhibits 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 from turning over which is needed for dissociation of topoisomerase II from its nucleic acid substrate. In other words, topoisomerase II stabilises the topoisomerase II complex after it has broken the DNA chain. This leads to topoisomerase II mediated DNA-cleavage, producing DNA breaks.^[8] The binding of topoisomerase II inhibitor prevents DNA repair by ligase.^[9]^[10]
Creates iron-mediated free oxygen radicals that damage the DNA, proteins and cell membranes.^[7]
Induces histone eviction from chromatin that deregulates DNA damage response, epigenome and transcriptome.^[11]

Cardiotoxicity[edit]

Anthracyclines are notorious for causing cardiotoxicity. This cardiotoxicity may be caused by many factors, which may include inhibition and/or poisoning of topoisomerase-IIB in cardiomyocytes,^[12] 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.^[13]

There exists evidence that the effect of cardiotoxicity increases in long-term survivors, from 2% after 2 years to 5% after 15 years.^[14]

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:^[13]

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.^[15]
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.^[16]
Longer infusion rates will result in a reduced plasma level and a much lower left ventricular peak concentration.^[13]

References[edit]

^ 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.
^ ^a ^b Weiss RB (December 1992). "The anthracyclines: will we ever find a better doxorubicin?". Semin. Oncol. 19 (6): 670–86. PMID 1462166. Cite uses deprecated parameters (help)
^ 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. Cite uses deprecated parameters (help)
^ 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. Cite uses deprecated parameters (help)
^ 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.
^ ^a ^b 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.
^ Pommier, Y., Leo, E., Zhang, H., Marchand, C. 2010. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem. Biol. 17: 421-433.
^ Osheroff Neil, Eukaryotic Topoisomerase II: characterisation of enzyme turnover, 1986, The Journal of Biological CHemistry, vol. 261, no. 21, pp. 9944-9950
^ Peter Buhl Jensen et al., Different modes of anthracycline interaction with topoisomerase II: Separate structures critical for DNA-cleavage, and for overcoming topoisomerase II-related drug resistance, 1993, Biochemical Pharmacology, vol. 45, no. 10, pp. 2025-2035
^ 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. PMID 23104132.
^ ^a ^b ^c 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). "Cardioprotective interventions for cancer patients receiving anthracyclines". In Van Dalen, Elvira C. 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.

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English Journal

Anesthesia for the Child with Cancer.

Latham GJ.Author information Department of Anesthesiology and Pain Medicine, Seattle Children's Hospital, University of Washington School of Medicine, 4800 Sand Point Way Northeast, MB.11.500.3, Seattle, WA 98105, USA. Electronic address: gregory.latham@seattlechildrens.org.AbstractChildren with cancer undergo a host of surgeries and procedures that require anesthesia during the various phases of the disease. A safe anesthetic plan includes consideration of the direct effects of tumor, toxic effects of chemotherapy and radiation therapy, the specifics of the surgical procedure, drug-drug interactions with chemotherapy agents, pain syndromes, and psychological status of the child. This article provides a comprehensive overview of the anesthetic management of the child with cancer, focuses on a systems-based approach to the impact from both tumor and its treatment in children, and presents a discussion of the relevant anesthetic considerations.
Anesthesiology clinics.Anesthesiol Clin.2014 Mar;32(1):185-213. doi: 10.1016/j.anclin.2013.10.002. Epub 2013 Dec 10.
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PMID 24491657

DNA topoisomerase II-dependent control of the cell cycle progression in root meristems of Allium cepa.

Zabka A, Polit JT, Bernasińska J, Maszewski J.Author information Department of Cytophysiology, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska 141/143, 90-236, Łódź, Poland.AbstractThe catalytic ability of DNA topoisomerases (Topo) to generate short-term DNA breaks allow these enzymes to play crucial functions in managing DNA topology during S-phase replication, transcription, and chromatin-remodelling processes required to achieve commitment for the onset and transition through mitosis. Our experiments on root meristem cells of onion (Allium cepa) were designed to gain insight into the contribution of Topo II to plant-specific progression throughout interphase and mitosis. Irrespective of the position of the cell in interphase, the immunofluorescence of Topo II revealed similar nuclear labelling pattern with well defined signals dispersed in the nucleoplasm and the cortical zone of the nucleolus. Only weak labelling was detected in metaphase and anaphase chromosomes. Experiments with two potent anti-Topo II agents, doxorubicin (DOX, an anthracycline) and a bisdioxopiperazine derivative, ICRF-193, suggest that the inhibition-mediated increase in Topo II immunofluorescence may represent a compensatory mechanism, by which an up-regulated expression of the enzyme tends to counteract the drug-induced loss of indispensable catalytic and relaxation functions. γ-H2AX immunolabelling seems to indicate that both DOX- and ICRF-193-induced alterations in cell cycle progression reflect primarily the activity of the G2/M DNA damage checkpoint. Our findings provide evidence for the plant-specific cell cycle control mechanism induced by Topo II inhibitors under DNA stress conditions.
Cell biology international.Cell Biol Int.2014 Mar;38(3):355-67. doi: 10.1002/cbin.10211. Epub 2013 Dec 3.
The catalytic ability of DNA topoisomerases (Topo) to generate short-term DNA breaks allow these enzymes to play crucial functions in managing DNA topology during S-phase replication, transcription, and chromatin-remodelling processes required to achieve commitment for the onset and transition throu
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New agents in locally advanced breast cancer.

Wilson S, Chia S.Author information BC Cancer Agency, Vancouver, British Columbia, Canada.AbstractPURPOSE OF REVIEW: Sequential anthracycline/taxane regimens are routinely used as neoadjuvant therapy (NAT) for locally advanced breast cancer. Unfortunately, the majority of patients do not achieve a pathological complete response (pCR). Efforts to improve pCR rates include the addition of novel targeted agents. The purpose of this article is to review recent developments in this area and to demonstrate the clinical and research advantages of a neoadjuvant platform for the evaluation of novel targeted therapy.
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Japanese Journal

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高橋勉
YAKUGAKU ZASSHI 131(3), 355-358, 2011
… To elucidate the mechanisms underlying the toxicity of anticancer drugs in greater detail, we performed a screen for determinants of sensitivity to adriamycin, an anthracycline antitumor antibiotic, using budding yeast as a model eukaryote. …
NAID 130000678897

Efficacy and safety of amrubicin hydrochloride for treatment of relapsed small cell lung cancer

Ogawara Daiki,Fukuda Minoru,Nakamura Yoichi,Kohno Shigeru
Cancer Management and Research 2(1), 191-195, 2010-08
… Amrubicin is a synthetic anthracycline agent with a similar structure to doxorubicin, in which the hydroxyl group at position 9 in amrubicin is replaced by an amino group to enhance efficacy. …
NAID 120002513789