Anthracycline
Anthracyclines (or anthracycline antibiotics) are a class of drugs used in cancer chemotherapy derived from Streptomyces bacterium [1] Streptomyces peucetius var. caesius.
These compounds are used to treat many cancers, including leukemias, lymphomas, 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 chemotherapeutic agents.[2][3][4] Their main adverse effect is cardiotoxicity, which considerably limits their usefulness. 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 (Adriamycin) was developed shortly after, and many other related compounds have followed, although few are in clinical use.[2]
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[edit] Examples
Available agents include:
- Daunorubicin (Daunomycin)
- Daunorubicin (liposomal)
- Doxorubicin (Adriamycin)
- Doxorubicin (liposomal)
- Epirubicin
- Idarubicin
- Valrubicin, used only to treat bladder cancer
- Mitoxantrone, anthracycline analog
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.
[edit] Mechanism of action
Anthracycline has three 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.[5]
- Inhibits topoiosomerase II enzyme, preventing the relaxing of supercoiled DNA and thus blocking DNA transcription and replication.
- Creates iron-mediated free oxygen radicals that damage the DNA and cell membranes.[5]
[edit] Cardiotoxicity
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, from 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 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. [6]
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 (echocardiogram or multi-gated acquisition “MUGA” scans) 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 to reduce plasma levels.[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.
[edit] See also
[edit] References
- ^ http://www.cancer.gov/templates/db_alpha.aspx?CdrID=44916
- ^ a b 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.
- ^ 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.
- ^ 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.
- ^ John Kenyon. Chemotherapy and cardiac toxicity - the lesser of two evils. Doctors Lounge Website. Available at: http://www.doctorslounge.com/index.php/blogs/page/14030. Accessed October 02 2010.
- ^ van Dalen EC, Caron HN, Dickinson HO, Kremer LC (2008). Van Dalen, Elvira C. ed. "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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