Transcript Anthracyclines

ANTHRACYCLINES
By Jessica Garcia and Megan Bullard
Why Anthracyclines?
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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?
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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
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Anthracyclines: An antibiotic used to treat many types
of cancer. Comes from certain strains of Streptomyces
bacteria.2
Streptomyces
bacteria
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Cancer: uncontrolled growth of abnormal cells. 3
Basic Terms and Definitions
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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
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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
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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.
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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?
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Chemical structures:
Daunorubicin
Doxyrubicin
What Are Anthracyclines?
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Chemical structures:
Valrubicin
Amrubicin
Most Commonly Used Anthracyclines
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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
6
What Are Anthracyclines?
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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
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What Are Anthracyclines?
Superoxide ion, hydrogen peroxide- produced after doxorubicin is
metabolized. These two products lead to DNA damage.
Its Uses
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Cancer Treatment:
 Breast cancer- specifically anthracyclines treat the
HER2+ breast cancer. They do not work on HER2breast cancer.8
Dividing breast
cancer cells
Its Uses
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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
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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
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Chronic administration of anthracyclines induces
cardiomyopathy and congestive heart failure which is
unresponsive to common medications for heart failure
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Second-generation analogs like epirubicin or idarubicin show
improvements in their therapeutic index, but the risk of inducing
cardiomyopathy is not improved. 11
The Side Effects
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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
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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
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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
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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
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A Recent Study
Implications for Future Use
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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
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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
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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
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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
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2. National Cancer Institute. 2012. http://www.cancer.gov/dictionary?cdrid=44916. Accessed April 2012.
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3. PubMed Health. 2012. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002267/. Accessed April 2012
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4. National Cancer Institute. 2012. http://www.cancer.gov/cancertopics/coping/chemo-side-effects/understandingchemo. Accessed April 2012.
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5. Kinsaw State University. 2012. http://chemcases.com/cisplat/cisplat13.htm. Accessed April 2012.
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6. Toxipedia. 2011. http://toxipedia.org/display/toxipedia/Anthracyclines.Accessed April 2012
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7. Robert, J., and Gianni, L. 1993. Pharmacokinetics and metabolism of anthracyclines. PubMed. 17: 219-252.
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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.
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9. Antman, K. and Chang, Y. 2000. Kaposi’s Sarcoma. The New England Journal of Medicine. 342:1027-1038.
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10. Barlogie, B. et al. 2004.Treatment of Multiple Myeloma. Blood. 103(1):20-32.
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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.
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15. Haynes et al. 2008.Immunogenic anti-cancer chemotherapy as an emerging concept. Current Opinion in Immunology. 20: 545-557.
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16. Gianni et al. 2009. Role of anthracyclines in the treatment of early breast cancer. Journal of clinical Oncology. 27: 4798-4808.
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17.Apetoh et al. 2008. Immunogenicity of anthracyclines:moving towards more personalized medicine.. Trends in Molecular Science. 14(4): 141-152.