By Jessica Garcia and Megan Bullard Anthracyclines By Jessica Garcia and Megan Bullard

Why Anthracyclines? We chose this group of toxins because of its relation to cancer and pharmaceuticals. It is rare that you will find a person that doesn’t know of someone who has had or still has cancer. There were over 1.5 million new cancer cases in 2011 in the United States. 1

Why Anthracyclines? New cancer cases in the United States for 2011. 1

Why Anthracyclines? As future pharmacists we wanted to know more about a group of drugs that treat various types of cancers. Specifically we wanted to look at the group’s history, uses, pharmacokinetics, side effects, recent studies, and implications for future use.

Basic Terms and Definitions Anthracyclines: An antibiotic used to treat many types of cancer. Comes from certain strains of Streptomyces bacteria.2 Cancer: uncontrolled growth of abnormal cells. 3 Streptomyces bacteria

Basic Terms and Definitions Chemotherapy: Cancer treatment that uses medicine to destroy cancer cells. Can be used alone or in combination with other treatments. 4 Second generation analogs: referring to new synthetic drugs that are improvements on previously existing treatments.5

History Anthracyclines are derived from mustard gasses which were used in chemical warfare during WWI. They were isolated and found to inhibit fast-growing cells from further growth. These cells included lymphoid and myeloid cells which are involved in the cancer lymphoma. WWII marked the beginning of a large scale production of antibiotics. A commonly used bacteria source for these antibiotics was Streptomyces.

History 1950’s French and Italian scientists worked together to create Daunorubicin, the first anthracyline ever developed. 1969- Daunorubicin was used to treat acute leukemia and lymphoma, however a common side effect was cardiotoxicity. Thus began the growth of a drug class. There are now over 2000 analogs, many of which are derivatives of Daunorubicin. 6

What Are Anthracyclines? Chemical structures: Daunorubicin Doxyrubicin

What Are Anthracyclines? Chemical structures: Valrubicin Amrubicin

Most Commonly Used Anthracyclines6 Daunorubicin- the original Anthracycline Doxorubicin- most commonly used Epirubicin- similar to doxorubicin Esorubicin-synthetic derivative of doxorubicin Aclarubicin- Less toxic than daunorubicin and doxorubicin Idarubicin- Most effective at penetrating cell membranes Amrubicin- new and less toxic Pirarubicin- used for doxorubicin resistant cells Valrubicin- specially used for bladder cancer

What Are Anthracyclines? Pharmacokinetics:6 Inhibition of DNA replication (nucleus and mitochondria) Inhibition of topoisomerase II Metabolism in the body (oxidation) 6 Release of free radicals (oxygen superoxides and hydrogen peroxide) Their main metabolic feature is the reduction of a ketone group to an hydroxyl group. Anthracyclines are characterized by a rapid distribution phase and a slow elimination phase7

What Are Anthracyclines? Superoxide ion, hydrogen peroxide- produced after doxorubicin is metabolized. These two products lead to DNA damage.

Its Uses Cancer Treatment: Breast cancer- specifically anthracyclines treat the HER2+ breast cancer. They do not work on HER2- breast cancer.8 Dividing breast cancer cells

Its Uses Cancer Treatment: Kaposi’s sarcoma- a cancer of the blood vessels caused by HHV8. It is treated by liposomal anthracyclines which are anthracyclines encased in small fat globules.9 Lesions caused Kaposi’s sarcoma

Its Uses Cancer Treatment: Multiple myeloma- recently started using liposomal anthracyclines to treat cancer of the plasma cells in bone marrow.10 Malignant plasma cells Multiple meyloma often causes “punched out” lytic lesions in the skull

The Side Effects Chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure which is unresponsive to common medications for heart failure Second-generation analogs like epirubicin or idarubicin show improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not improved. 11 Down regulation citation :

The Side Effects Down regulation of the GATA4 gene a survival factor of cardiac muscle cells. Down regulation leads to apoptosis (cell suicide).12 GATA4 is on the eighth chromosome, from base pair 11, 561,716 to 11,617,508

The Side Effects The degree of myocardial toxicity due to anthracyclines may be directly related to the accumulation of drug metabolites in the myocardium. 13 .

The Side Effects Few cancers are unresponsive (e.g. colon cancer) Recently there has been an emergence of clones of tumors resistant to anthracyclines.14 Survival rates in breast cancer patients: First line represents those who are treated with anthracyclines once. 2nd or more represents those who have had 2 or more treatments of anthracyclines. The latter developed resistance.

A Recent Study Anthracyclines have recently been shown to stimulate our immune response to tumor cells. Does so by: Inducing translocation of intracellular calreticulin (CRT) so that it is expressed on the dying tumor cell membrane. This allows dendritic cells to phagocytize the dying cells which can then stimulate anti-tumor T cell responses. Causing the release of HMGB1, which is a protein released from dying cells during late stage apoptosis. HMGB1 can signal tissue injury and initiate an inflammatory response through binding TLR4. 15

A Recent Study

Implications for Future Use In order to improve anthracyclines, we must be able to make them less toxic, and yet still effective. In a study Gianni et al., the question, “Should anthracyclines be replaced by taxanes” is raised. Sufficient evidence was found, and it was suggested that combining taxanes and anthracyclines may be our best option. 16 This same study found that genetic markers may have a role in predicting an individual’s susceptibility to cardiotoxicity.

Implications for Future Use The recent study on this group of drugs and their effects on the immune system can help us determine better dosage timing. Also, from a biotechnological point of view, we can now make a drug-screening program that could select products capable of translocating CRT to the plasma membrane of tumor cells.17

Conclusions We found the history behind the creation of anthracyclines to be quite original. Severe cardiotoxicity was the most common adverse side effect. While new synthetic drugs attempt to lessen this effect, it is still prevalent. The recent discovery of anthracyclines effects on our immune system has brought to light not only a better understanding of the drugs, but also allows us to form better solutions based on chemotherapy and immunotherapy.

Sources 1.American Cancer Society. 2011. Cancer Disparities and Premature Deaths. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-029771.pdf Accessed April 2012 2. National Cancer Institute. 2012. http://www.cancer.gov/dictionary?cdrid=44916. Accessed April 2012. 3. PubMed Health. 2012. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002267/. Accessed April 2012 4. National Cancer Institute. 2012. http://www.cancer.gov/cancertopics/coping/chemo-side-effects/understandingchemo. Accessed April 2012. 5. Kinsaw State University. 2012. http://chemcases.com/cisplat/cisplat13.htm. Accessed April 2012. 6. Toxipedia. 2011. http://toxipedia.org/display/toxipedia/Anthracyclines.Accessed April 2012 7. Robert, J., and Gianni, L. 1993. Pharmacokinetics and metabolism of anthracyclines. PubMed. 17: 219-252. 8. Gennari, A. et al. 2008. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. Journal of the National Cancer Institute. 100(1):14-20. 9. Antman, K. and Chang, Y. 2000. Kaposi’s Sarcoma. The New England Journal of Medicine. 342:1027-1038. 10. Barlogie, B. et al. 2004.Treatment of Multiple Myeloma. Blood. 103(1):20-32. 11. Minnoti et al. 2004. Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity. Pharmacological Reviews. 56:185-229. 12. Park et al., 2011. Mechanism of anthraccline-mediated down-regulation of GATA4 in the heart. Cardiovascular Research. Vol. 90 (1): 97-104. 13. Jaenke, R.S., Deprez-DeCampeneere, and Trouet, A. 1980. Cardiotoxicity and comparative pharmacokinetics of six anthracyclines in the rabbit,.Cancer Research. 40: 3530. 14. Walder, Fuks and Wiernik, 1986 . Phase I and II agents in cancer therapy: I. Anthracylines and related compounds, The Journal of Clinical Pharmacology. 26(7): 491-509. 15. Haynes et al. 2008.Immunogenic anti-cancer chemotherapy as an emerging concept. Current Opinion in Immunology. 20: 545-557. 16. Gianni et al. 2009. Role of anthracyclines in the treatment of early breast cancer. Journal of clinical Oncology. 27: 4798-4808. 17.Apetoh et al. 2008. Immunogenicity of anthracyclines:moving towards more personalized medicine.. Trends in Molecular Science. 14(4): 141-152.