Anthracyclines

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7,8,9,10-tetrahydrotetracene-5,12-dione: basic structure of the aglycone of the anthracyclines

Anthracyclines or anthracyclines are a group of substances isolated from Streptomyces species with antibiotic and anti- neoplastic effects.

Chemically, they are glycosides with a cyclohexane - fused anthraquinone skeleton, the 7,8,9,10-tetrahydrotetracene-5,12-dione , as an aglycon . In addition to other substituents , the anthracyclines have several hydroxyl groups . The glycosidic bond with the carbohydrate is in many cases on the D-ring of the aglycone.

They are related to the angucyclines , which differ in the cyclohexane ring fused to the anthraquinone at an angle (lat .: angulus ) .

Anthracyclines are used as cytotoxic drugs in chemotherapy against various types of cancer . They include: B. epirubicin , idarubicin , doxorubicin , daunorubicin , pirarubicin , zorubicin , aclarubicin and caminomycin .

history

The first anthracycline, daunorubicin, was first isolated from Streptomyces peucetius in 1963 in Italy (by Farmitalia ) and France (by Rhône-Poulenc ) . A cytotoxic effect against leukemia cells has been identified. Doxorubicin was isolated in 1969 by Farmitalia from the mutated strain Streptomyces peucetius caesius and had a cytotoxic effect even against solid tumors .

Biological importance

Anthracyclines work, among other things, by binding to the enzyme topoisomerase II α. Topoisomerase IIα is a key enzyme in cell division . In addition, anthracyclines intercalate into the DNA and thus prevent further nucleic acid synthesis. Another mechanism of action is that biotransformation creates free radicals that can create double-strand breaks in the DNA and lead to DNA adducts . Histones also become detached from DNA. Furthermore, anthracyclines can lead to a deficient function of the mitochondria . Furthermore, the binding of the anthracyclines to the cell membrane increases their permeability and fluidity, which leads to increased death of the affected cell.

Anthracyclines intervene in fundamental biochemical reaction processes and impair metabolic processes in bacteria as well as in animal cells. This results in an antibiotic effect. Daunorubicin, for example, has weak activity against gram-negative bacteria that is not used therapeutically.

Cardiotoxicity

Due to the rapid growth of cancer cells, anthracyclines disrupt them more than healthy cells. However, healthy body cells are also attacked, which can lead to serious, sometimes irreversible side effects such as disorders of the bone marrow and especially the heart . There is a risk of cardiomyopathy with irreversible heart failure . This undesirable effect occurs through the inhibition of the topoisomerase IIβ, which is the only topoisomerase in myocardial cells, and through the formation of radicals in myocardial cells. The iron chelator dexrazoxane was developed to reduce cardiotoxicity . Furthermore, liposomal drug formulations reduce the side effect. A lower infusion rate results in lower peak concentrations in the left ventricle .

Another problem in therapy with anthracylins is the resistance that a tumor can develop. Approaches to the structural change of the anthracyclines to better overcome the blood-brain barrier are investigated.

literature

  • Anthracyclines Chemistry and Biology I . Biological Occurrence and Biosynthesis, Synthesis and Chemistry. In: Karsten Krohn (Ed.): Topics in Current Chemistry . No. 282 . Springer-Verlag, Berlin, Heidelberg 2008, ISBN 978-3-540-75814-3 ( limited preview in Google book search).
  • Anthracycline Chemistry and Biology II . Mode of Action, Clinical Aspects and New Drugs. In: Karsten Krohn (Ed.): Topics in Current Chemistry . No. 283 . Springer-Verlag, Berlin, Heidelberg 2008, ISBN 978-3-540-75812-9 ( limited preview in the Google book search).
  • Anke Kruger, Leszek Wojnowski: Cardiotoxicity of anthracyclines - an unsolved problem , Deutsches Ärzteblatt, vol. 103, issue 37, September 15, 2006.

Individual evidence

  1. ↑ Hartmut Laatsch, Serge Fotso: Naturally Occurring Anthracyclines . In: Karsten Krohn (Ed.): Anthracycline Chemistry and Biology . No. I . Springer-Verlag, Berlin, Heidelberg 2008, ISBN 978-3-540-75814-3 , pp. 4th ff . ( limited preview in Google Book search).
  2. ^ A b Q. Ashton Acton: Anthracyclines — Advances in Research and Application: 2013 Edition. Scholarly Editions, 2013, ISBN 978-1-4816-7278-8 , p. 23.
  3. ↑ Grein A, et al. Descrizione e classificazione di un attinomicete (Streptomyces peucetius sp. Nova) produttore di una sostanza ad attivita antitumorale. Giorn. Microbiol. 11, 1963, pp. 109-118.
  4. ↑ M. Dubost, P. Ganter, R. Maral, L. Ninet, S. Pinnert, J. Preudhomme, GH Werner: [A NEW ANTIBIOTIC WITH CYTOSTATIC PROPERTIES: RUBIDOMYCIN.] In: CR Hebd. Seances Acad. Sci. , 257, 1963, pp. 1813-1815; Digitized on Gallica ; PMID 14090569 .
  5. ↑ RB Weiss: The anthracyclines: will we ever find a better doxorubicin? In: Seminars in Oncology . Volume 19, Number 6, December 1992, pp. 670-686, PMID 1462166 .
  6. ^ A b c Jan HM Schellens: Cancer Clinical Pharmacology. OUP Oxford, 2005, ISBN 978-0-19-262966-1 , pp. 117-119.
  7. ↑ F. Arcamone, G. Cassinelli, G. Fantini, A. Grein, P. Orezzi, C. Pol, C. Spalla: Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. Caesius. In: Biotechnology and Bioengineering . Volume 11, Number 6, November 1969, pp. 1101-1110, doi: 10.1002 / bit.260110607 , PMID 5365804 .
  8. ↑ Piccart-Gebhart, MJ (2006): Anthracyclines and the tailoring of treatment for early breast cancer. In: N. Engl. J. Med. Vol. 354, pp. 2177-2179; PMID 16707755 .
  9. ↑ B. Pang, X. Qiao, L. Janssen, A. Velds, T. Groothuis, R. Kerkhoven, M. Nieuwland, H. Ovaa, S. Rottenberg, O. van Tellingen, J. Janssen, P. Huijgens, W. Zwart, J. Neefjes: Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. In: Nature Communications . Volume 4, 2013, p. 1908, doi: 10.1038 / ncomms2921 , PMID 23715267 , PMC 3674280 (free full text).
  10. ^ A. Mordente, E. Meucci, A. Silvestrini, GE Martorana, B. Giardina: Anthracyclines and mitochondria. In: Advances in Experimental Medicine and Biology . Volume 942, 2012, pp. 385-419, doi : 10.1007 / 978-94-007-2869-1_18 , PMID 22399433 .
  11. ↑ T. Dingermann, Karl Hiller, G. Schneider, I. Zündorf: Schneider drug drugs. 5th edition. Elsevier, 2004. p. 584 ff.
  12. ↑ TK Sethi, B. Basdag, N. Bhatia, J. Moslehi, NM Reddy: Beyond Anthracyclines: Preemptive Management of Cardiovascular Toxicity in the Era of Targeted Agents for Hematologic Malignancies. In: Current Hematologic Malignancy Reports . Volume 12, Number 3, June 2017, pp. 257-267, doi: 10.1007 / s11899-017-0369-y , PMID 28233150 .
  13. ^ S. Zhang, X. Liu, T. Bawa-Khalfe, LS Lu, YL Lyu, LF Liu, ET Yeh: Identification of the molecular basis of doxorubicin-induced cardiotoxicity. In: Nature Medicine . Volume 18, Number 11, November 2012, pp. 1639-1642, doi: 10.1038 / nm.2919 , PMID 23104132 .
  14. ↑ A. Mordente, E. Meucci, GE Martorana, D. Tavian, A. Silvestrini: Topoisomerases and Anthracyclines: Recent Advances and Perspectives in Anticancer Therapy and Prevention of Cardiotoxicity. In: Current Medicinal Chemistry . Volume 24, number 15, 2017, pp. 1607-1626, doi: 10.2174 / 0929867323666161214120355 , PMID 27978799 .
  15. ↑ DW Edwardson, R. Narendrula, S. Chewchuk, K. Mispel-Beyer, JP Mapletoft, AM Parissenti: Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines. In: Current Drug Metabolism . Volume 16, number 6, 2015, pp. 412-426, PMID 26321196 , PMC 5398089 (free full text).
  16. ↑ EC van Dalen, HN Caron, HO Dickinson, LC Kremer: Cardioprotective interventions for cancer patients receiving anthracyclines. In: The Cochrane Database of Systematic Reviews . Number 6, June 2011, p. CD003917, doi: 10.1002 / 14651858.CD003917.pub4 , PMID 21678342 .
  17. ↑ EA Forssen, ZA Tökes: In vitro and in vivo studies with adriamycin liposomes. In: Biochemical and Biophysical Research Communications . Volume 91, Number 4, December 1979, pp. 1295-1301, PMID 526304 .
  18. ^ G. Minotti, P. Menna, E. Salvatorelli, G. Cairo, L. Gianni: Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. In: Pharmacological Reviews . Volume 56, Number 2, June 2004, pp. 185-229, doi: 10.1124 / pr.56.2.6 , PMID 15169927 .
  19. ^ A b M. da Ros, AL Iorio, M. Lucchesi, A. Stival, M. de Martino, I. Sardi: The Use of Anthracyclines for Therapy of CNS Tumors. In: Anti-Cancer Agents in Medicinal Chemistry . Volume 15, number 6, 2015, pp. 721-727, PMID 25846760 , PMC 4997942 (free full text).

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