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This Article Appeared in a Journal Published by Elsevier. the Attached Copy Is Furnished to the Author for Internal Non-Commerci This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright Author's personal copy Pharmacology & Therapeutics 133 (2012) 26–39 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Anthracyclines and ellipticines as DNA-damaging anticancer drugs: Recent advances Rene Kizek a,⁎, Vojtech Adam a, Jan Hrabeta b, Tomas Eckschlager b, Svatopluk Smutny c, Jaroslav V. Burda d, Eva Frei e, Marie Stiborova f a Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic b Department of Paediatric Haematology and Oncology, 2nd Medical School, Charles University and University Hospital Motol, V Uvalu 84, CZ-150 06 Prague 5, Czech Republic c 1st Department of Surgery, 2nd Medical School, Charles University and University Hospital Motol, V Uvalu 84, CZ-150 06 Prague 5, Czech Republic d Department of Chemical Physics and Optics, Faculty of Mathematics and Physics, Charles University, Ke Karlovu 3, CZ-121 16 Prague 2, Czech Republic e Division of Preventive Oncology, National Center for Tumor Diseases, German Cancer Research Center, In Neuenheimer Feld 280, D-69120 Heidelberg, Germany f Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, CZ-128 40 Prague 2, Czech Republic article info abstract Keywords: Over the past forty years, anthracyclines and ellipticines have attracted attention as promising cytostatics. In Anthracyclines this review, we focus on their mechanisms of cytoxicity, DNA-damaging effects and adverse side-effects. We Ellipticine also summarize ways to enhance the therapeutic effects of these drugs together with a decrease in their Adduct formation adverse effects. Current drug design strategies are focused on drug bioavailability and their tissue targeting, Nanocarriers whereas drug delivery to specific intracellular compartments is rarely addressed. Therefore, therapies utilizing the antineoplastic activities of anthracyclines and ellipticines combined with novel strategies such as nanotechnologies for safer drug delivery, as well as strategies based on gene therapy, could significantly contribute to medical practice. © 2011 Elsevier Inc. All rights reserved. Contents 1. DNA-adducts and their biological significance ............................... 26 2. Ellipticines ............................................... 27 3. Anthracyclines..............................................30 27 4. How to scavenge reactive oxygen species produced by the drugs . ...................33 28 5. Nanocarriers as a new tool in the targeting of ellipticines and anthracyclines ................34 30 6. Conclusion and future perspectives ....................................36 30 Acknowledgments ..............................................36 30 References ..................................................36 31 1. DNA-adducts and their biological significance reactive nature) or (ii) otherwise interacts with a target to cause toxicity. Examples (i) and (ii) are (usually) distinguished by (i) their capability for The potential of chemicals (drugs) to induce toxic effects and DNA a genotoxic response vs. (ii) a tendency to act by causing increased cell damage depends on their metabolism. If the administered drug has a proliferation, although these two phenomena are not mutually exclusive. direct toxicity of its own (or acts directly on DNA or a receptor to produce The list of potential DNA, lipid, and protein targets with reactive toxicity), then metabolism of the drug, mediated by many enzymes such electrophiles and radicals is extensive. With DNA, understanding at least as cytochromes P450 (CYP), peroxidases or NAD(P)H:quinoneoxidor- some of the most relevant gene responses and their mechanisms is eductase, may reduce its toxicity if the product generated by such becoming possible. enzymes has less inherent toxicity. Another case is the transformation of Genetic damage that produces a heritable loss of growth control, an administered drug to another that either (i) binds covalently to differentiation or apoptosis comprises a major mechanism of macromolecules such as DNA (usually because of its electrophilic or other carcinogenesis. Exposure to drugs having genotoxic side effects results in structural damage to DNA, which occurs primarily as the covalent binding of chemicals and is referred to as drug–DNA adduct ⁎ Corresponding author. Tel.: +420 5 4513 3350; fax: +420 5 4521 2044. formation (Hemminki et al., 1994). Numerous types of DNA adducts E-mail address: [email protected] (R. Kizek) have been identified. Generally, nitrogen and oxygen atoms on the bases 0163-7258/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2011.07.006 Author's personal copy R. Kizek et al. / Pharmacology & Therapeutics 133 (2012) 26–39 27 are active sites. There have been reactions described on the N2, N-3, O6 ma, sarcomas, myelomas, lymphomas, colon adenocarcinoma, lung and N-1 sites of guanine, N-1, N-3, N6 and N-7 sites of adenine, O2,N-3 carcinoma, diverse brain tumors, osteosarcoma, breast cancer and and N4 sites of cytosine and O2 and O4 sites of thymine. There are also neuroblastomas, which were killed at concentrations ranging from some reactions known on the phosphate and deoxyribose moieties. 10−10 to 10−6 M (for an overview, see Arguello et al., 1998; Garbett & Guanine is the most reactive base of the four DNA bases. Guanines Graves, 2004; Stiborova et al., 2006b; Tian et al., 2008). One of the modified on N2, O6 and C-8 hydroxylated guanine [8-hydroxyguanine ellipticine derivatives, 9-hydroxy-N2-methylellipticine (NSC (8-OH-Gua)] are well-known adducts (Fraga et al., 1990; Shigenaga & 264-137), selected for a phase I and later a phase II trial in human Ames, 1991). Exposure to some aldehydes and ultraviolet rays is cancer, seems to particularly improve the condition of patients responsible for the formation of cross-links between the amino groups suffering from breast cancer (Dodion et al., 1982), especially after it of bases in DNA. In addition, intrastrand cross-linking can cause miscopy has metastasized to the bone (Paoletti et al., 1980; Juret et al., 1982; of DNA (Matsuda et al., 1998). The above-mentioned DNA damage is Rouesse et al., 1985). Activity against anaplastic thyroid carcinoma generally considered to be causative and directly related to tumor and ovarian carcinoma has also been observed. formation (Lutz, 1986; Poirier, 1996; Otteneder & Lutz, 1999; Hemminki The main reason for the interest in ellipticine and its derivatives for et al., 2000; Poirier et al., 2000; Wiencke, 2002). Indeed, associations clinical purposes is their high efficiencies against several types of have been observed between DNA adduct formation, mutagenesis cancer, their rather limited side effects and, in particular, their lack of (Poirier et al., 2000; Wiencke, 2002), and tumorigenesis (Otteneder & hematologic and hepatic toxicity (Auclair, 1987). In patients that Lutz, 1999; Poirier et al., 2000), while reductions in DNA adduct levels received a weekly 80 mg/m2 of 9-hydroxy-N2-methylellipticine, no renal have been associated with chemoprevention (Wiencke, 2002). There- trouble was observed during the first year, but 2 deaths from renal fore, it is not surprising that investigation of the mechanisms insufficiency occurred during the 15th and 18th months of treatment. responsible for the toxicity of DNA adducts, which are essential for Nevertheless, the most frequent side effect was digestive troubles (nausea cancer development, attracts the attention of many laboratories. and vomiting in one-third of the patients), which rarely results in DNA damage is, however, also employed for cancer treatment. In termination of the treatment, hypertension, muscular cramps, chronic other words, many efficient anticancer drugs are based on the fatigue (which can be very pronounced), mouth dryness, mycosis of the modification of DNA in cancer cells. Indeed, several cytostatics are tongue and esophagus (Paoletti et al., 1980). In addition, the mutagenicity capable of forming DNA-adducts. The aim of this review is to furnish of ellipticines should be evaluated as a potential risk factor. Namely, most information about two similar classes of cytostatics acting as DNA- ellipticines are mutagenic to Salmonella typhimurium Ames tester strains, damaging agents, doxorubicin and its derivatives and ellipticines. In bacteriophage T4, Neurospora crassa, and mammalian cells, as well as addition, their metabolism and mechanisms of action based on induce prophage lambda in Escherichia coli (for an overview, see Stiborova interactions with DNA and other mechanisms (interaction with et al., 2001). In addition, ellipticine provided positive results in a mouse topoisomerases II, generation of free radicals, etc.) are reviewed, lymphoma assay (Moore et al., 1987),
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