Doxorubicin in Breast Cancer

 

Doxorubicin is an antitumour antibiotic belonging to the family of anthracycline
which the classical ones (e.g. rhodomycin) being cytotoxic and having narrow
therapeutic windows. But doxorubicin has been given interest because of its
anticancer effects in the treatment of many cancers including breast cancer,
bladder cancer and lymphoma 1. Doxorubicin (sold under common
trade name Adriamycin) is commonly used in combination with other chemotherapy
drugs with an injection into the vein being the mainly route of administration.

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The structure of the drug

2

 

Disease target

 

Doxorubicin is indicated for the control and treatment of a variety of human
cancers including breast,
ovarian, lung, bladder, thyroid, liver, and gastric cancers; Hodgkin’s and
non-Hodgkin’s lymphomas; Wilm’s tumor; soft-tissue sarcoma; neuroblastoma; and
acute lymphoblastic leukemia. It is also used as part of the main adjuvant
therapy in women with confirmation of an axillary lymph node inclusion
following a resection of primary breast cancer 4.

 

Molecular target

 

Doxorubicin works mainly on the DNA. It works
on the DNA in several ways with one being the intercalation (the squeezing of
the drug between the base pairs of the DNA). This then leads
to alteration of the DNA structure and prevents the DNA from exercising its
normal functions. Doxorubicin also acts on the enzyme topoisomerase II which is
responsible for excising both strands of DNA helix at the same time which the purpose
of controlling supercoils and tangles. This can lead to the termination of both
normal cells (via topoisomerase II?) and in tumour cells (via topoisomerase II?) 5. The drug produces lipid
molecules known as ceramides which stimulate the cleaving of CREB3L1. Over
expression of CREB3L1 makes the tumour cells more sensitive to doxorubicin
which results in altered gene that may contribute to the efficacy of the drug 6. 
Doxorubicin is also suspected to inhibit polymerase
activity, affect regulation of gene expression, and also production of free
radical damage to DNA 7.

 

 

Mechanism of action

9

 

Doxorubicin is also known to to work by specific
intercalation of the planar anthracycline nucleus with the DNA double helix. In
this process, the drug is intercalated into the parts of the DNA free of nuclear
proteins. This then leads to alteration of the DNA conformation which extends
to the histone octamer leading to the chromatin unfolding followed by
aggregation 10.

 

Topoisomerase II is an enzyme which cuts both strands of DNA helix at
the same time which the purpose of controlling supercoils and tangles. This can
lead to the termination of both normal cells (via
topoisomerase II?) and in tumour
cells (via topoisomerase II?) that
are susceptible to doxorubicin 11. Doxorubicin acts by inhibiting
topoisomerase II activity by stabilizing the DNA-topoisomerase II complex. Some
of rings on doxorubicin do not intercalate into the DNA and this leads to the
sustaining of the of the DNA-topoisomerase II complex. Since the DNA nicks
cannot be sealed, it leads to the build up of damage to the DNA which leads to
growth inhibition in the G1 and G2 phase hence leading to apoptotic cell death 12.

 

Pharmacokinetics

 

The
toxic effects of doxorubicin is related to its peak concentration making the
rate of administration of the drug very vital. It is recommended to dilute the
drug with 0.9% sodium chloride over a 30-60minutes infusion or a fast running
IV drip. This is because higher peak concentrations may result from rapid
intravenous bolus. Slower infusion rates also result in a greater area under
the curve and a longer distribution phase than a faster infusion rate and
reduce toxic effects. Doxorubicin is metabolized in the liver and excreted in
bile 13. Doxorubicin can undergo 3
metabolic routes: one-electron reduction, two-electron reduction and
deglycosidation. Doxorubicin is widely distributed with highest concentrations
in the liver, spleen, kidney, heart, small intestines, lung; its crosses the
placenta so can be found in breast milk. Doxorubicinol is the main active metabolite of doxorubicin of which 50-80% is bound to plasma protein. Doxorubicin does not cross
the blood brain barrier. Elimination is mainly in bile (40-50%) within 5days and
5-12% through urine as the drug and its metabolites over 5 days. The distributive half-life is 5 minutes with the terminal half life of the
drug is estimated to be 20-48 hours 14.

 

Pathophysiology

 

Doxorubicin is reduced by NADH dehydrogenase in
the respiratory complex I of the mitochondria to form a semiquinone radical
which in turn can also react with a molecule of oxygen to form a superoxide radical
15. The formation of this free radical ends up producing toxic effects
in cardiomyocites. A hydroxyl radical and hydrogen peroxide are then produced
following a series of redox reactions 16. The conversion of hydrogen peroxide to a hydroxyl
radical which is catalyzed by the formation of doxorubicin-iron complex
generates a reactive oxygen species 17. Cardiomyocites are very sensitive to the oxidant
stress that is caused by doxorubicin. The long term cardiotoxicity caused by
doxorubicin is characterized as a type I cardiotoxicity: cardiomyocyte death
either through apoptosis or necrosis with the result not being reversible. With
doxorubicin chemotherapy, a reduction in the left ventricular ejection fraction
(LVEF) which may be asymptomatic was seen following a cumulative doses of >350 mg/m2 18. PEGylated
liposomal is a form of doxorubicin delivery which reduces the cardiotoxicity by
reducing the oxidative stress. Some beta-adrenergic receptor blockers such as
Carvedilol has been suggested to possess some protection against left
ventricular dysfunction induced by doxorubicin through its antioxidant characteristics
19.

 

Rationale for its
prescription

 

Due
to the cardiotoxic effects doxorubicin has a drug of choice, it still proves
problematic in its use as an agent for breast cancer chemotherapy. Nonetheless,
doxorubicin belongs to an important class of drugs in the treatment of cancer. In
the administration of doxorubicin, cardioprotective therapies can be introduced
at early stages especially in patients with high risk of developing left
ventricular dysfunction induced by the drug. Beta blockers (especially
Carvedilol) and Angiotensin II Receptor Blockers (ACE) inhibitors (especially
enalapril) prevents decline in LVEF and late decline in LVEF respectively 20,21.

Recent data shows that 31% of patients on doxorubicin chemotherapy with their
decrease in LVEF being asymptomatic receive an ACE inhibitor or an angiotensin
receptor blocker. A beta blocker received by 35% with 42% being referred to see
cardiologist 22. Doxorubicin is hence used as
an effective treatment option for breast cancer with effective preventative
therapies to prevent the cardiotoxic effects it may produce. The effective
communication between cardiologist and oncologist is invaluable in monitoring
patients on this drug and making sure they receive effective treatment and all
necessary steps taken to prevent and reduce the risk of its cardiotoxic side
effect.  

 

 

 

 

 

 

 

References.

 

1 Arcamone, Federico. (1983). Structure-Activity Relationships in
Doxorubicin Related Compounds. 111-133. DOI:
10.1007/978-94-009-6798-4_7

 

2 PubChem. Doxorubicin.

Available from https://pubchem.ncbi.nlm.nih.gov/compound/doxorubicin#section=Top. (Accessed on
02/11/2017).

 

3 Arcamone F. et al. (1972)
Structure and Physicochemical Properties of Adriamycin (Doxorubicin). In:
Carter S.K., Marco A.D., Ghione M., Krakoff I.H., Mathé G. (eds) International Symposium on Adriamycin.

Springer, Berlin, Heidelberg. DOI: https://doi.org/10.1007/978-3-642-95227-2_2

 

4 Prendergast
G.C. (ed.), Jaffee E.M (ed). Cancer Immunotherapy: Immune Suppression and
Tumor Growth. Academic Press; 2007.

Ebook ISBN 9780080521855.

 

5 Zhang S, Liu X, Bawa-Khalfe T, Lu L.S, Lyu Y.L, Liu L.F. (2012).
Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 18:1639–1642.

Available from: https://doi.org/10.1038/nm.2919

 

6 Denard B, Lee C, Ye J.

(2012). Doxorubicin blocks proliferation of cancer cells
through proteolytic activation of CREB3L1. eLife 1:e00090.

Available from: https://doi.org/10.7554/elife.00090

 

7 DrugBank. Doxorubicin. Available from: http://www.drugbank.ca/drugs/DB00997

 

8 Denard B, Seemann J, Chen Q,
Gay A, Huang H, Chen Y. (2011).
The membrane-bound transcription factor CREB3L1 is activated in response to
virus infection to inhibit proliferation of virus-infected cells. Cell Host Microbe 10:65–74.

Available from: https://doi.org/10.1016/j.chom.2011.06.006

 

9 Denard B, Lee C, Ye J.

(2012). Doxorubicin blocks proliferation of cancer cells
through proteolytic activation of CREB3L1. eLife 1:e00090.

Available from: https://doi.org/10.7554/elife.00090

 

10 Rabbani, A. and J. Davoodi, Effects of anthracycline
antibiotic, daunomycin on thymus chromatin: the role of chromosomal proteins. Gen Pharmacol, 1994. 25(4):
p. 787-93

 

11 Zhang S, Liu X, Bawa-Khalfe T, Lu L.S,
Lyu Y.L, Liu L.F. (2012).
Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 18:1639–1642.

Available from: https://doi.org/10.1038/nm.2919

 

12 Perego,
P., et al., Role of apoptosis and apoptosis-related genes in
cellular response and antitumor efficacy of anthracyclines. Curr Med Chem, 2001. 8(1):
p. 31-7

 

13 Dobson J.M, Hohenhaus A.E, Peaston
A.E. Cancer Chemotherapy In: Small Animal Clinical Pharmacology. Second
Edition. 2008, Pages 330–366.

Available from: https://doi.org/10.1016/B978-070202858-8.50017-8

 

14 Product Monograph: Adriamycin® PFS (doxorubicin). Pfizer Canada, 2014

 

15 Davies KJ, Doroshow JH. Redox cycling of
anthracyclines by cardiac mitochondria I Anthracycline radical formation by
NADH dehydrogenase. J Biol Chem. 1986;261(7
):3060–7. Pubmed

 

16 Doroshow
JH, Davies KJ. Redox cycling of anthracyclines by cardiac mitochondria.II.

Formation of superoxide anion hydrogen peroxide and hydroxyl radical. J Biol Chem. 1986;261(7 ):3068–74. Pubmed

 

17 Kotamraju
S, Chitambar CR, Kalivendi SV, et al. Transferrin receptor-dependent iron
uptake is responsible for doxorubicin-mediated apoptosis in endothelial cells
role of oxidant-induced iron signaling in apoptosis. J Biol Chem. 2002;277(19 ):17179–87 Pubmed

 

18
Buzdar AU, Marcus C, Smith TL, et
al. Early and delayed clinical cardiotoxicity of doxorubicin. Cancer. 1985;55(12 ):2761–5

 

19 Oliveira PJ, Bjork JA, Santos
MS, et al. Carvedilol-mediated antioxidant protection against
doxorubicin-induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol. 2004;200(2 ):159–68. PubMed

 

20
Cardinale D, Colombo A, Sandri MT,
et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk
patients by angiotensin-converting enzyme inhibition. Circulation. 2006;114(23 ):2474–8. PubMed

 

21 Kalay N, Basar E, Ozdogru I, et al.

Protective effects of carvedilol against anthracycline-induced
cardiomyopathy. J Am Coll Cardiol. 2006;48(11
):2258–62. PubMed

 

22 Yoon GJ, Telli ML, Kao DP, et
al. Left ventricular dysfunction in patients receiving cardiotoxic cancer
therapies are clinicians responding optimally? J Am Coll Cardiol. 2010;56(20 ):1644–50. PMC free article PubMed

 

 

 

 

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