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Daunorubicin.png
Daunorubicin, the prototypical anthracycline

Doxorubicin chemical structure.png
Epirubicin.png
Idarubicin.svg

Anthracyclines (or anthracycline antibiotics) are a class of drugs used in cancer chemotherapy derived from Streptomyces bacteria [1] (more specifically, Streptomyces peucetius var. caesius).[2]

These compounds are used to treat a wide range of cancers, including leukemias, lymphomas, and breast, uterine, ovarian, and lung cancers.

The anthracyclines are some of the most effective anticancer treatments ever developed and are effective against more types of cancer than any other class of chemotherapy agents.[3][4][5] Their main adverse effects are heart damage (cardiotoxicity), which considerably limits their usefulness, and vomiting.

The first anthracycline discovered was daunorubicin (trade name Daunomycin), which is produced naturally by Streptomyces peucetius, a species of actinobacteria. Doxorubicin (Adriamycin) was developed shortly after, and many other related compounds have followed, although few are in clinical use.[3]

Contents

Examples

Available agents include:

Since they are antibiotics, anthracyclines can kill or inhibit the growth of bacteria, but because they are so toxic to humans, they are never used to treat infections.

Mechanism of action

Anthracycline has three mechanisms of action:

  1. Inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells.[6]
  2. Inhibits topoiosomerase II enzyme, preventing the relaxing of supercoiled DNA and thus blocking DNA transcription and replication.
  3. Creates iron-mediated free oxygen radicals that damage the DNA and cell membranes.[6]

Cardiotoxicity

As well as many of the expected adverse reactions of chemotherapeutic agents, anthracyclines are notorious for causing cardiotoxicity. This cardiotoxicity may be caused by many factors, which may include interference with the ryanodine receptors of the sarcoplasmic reticulum in the heart muscle cells, free radical formation in the heart or from buildup of metabolic products of the anthracycline in the heart. The cardiotoxicity often presents as EKG changes and arrhythmias, or as a cardiomyopathy leading to congestive 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. [7]

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.[8] The liposomal formulations of daunorubicin and doxorubicin appear to be somewhat less toxic to cardiac tissue than the non-liposomal form.

See also

References

  1. ^ http://www.cancer.gov/templates/db_alpha.aspx?CdrID=44916
  2. ^ Streptomyces peucetius var. caesius
  3. ^ a b Weiss RB (December 1992). "The anthracyclines: will we ever find a better doxorubicin?". Semin. Oncol. 19 (6): 670–86. PMID 1462166.  
  4. ^ 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.  
  5. ^ 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.  
  6. ^ 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.
  7. ^ 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.  
  8. ^ van Dalen EC, Caron HN, Dickinson HO, Kremer LC (2008). "Cardioprotective interventions for cancer patients receiving anthracyclines". Cochrane Database Syst Rev (2): CD003917. doi:10.1002/14651858.CD003917.pub3. PMID 18425895.  







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