Anthracyclines play a vital role in treating many forms of cancer.

Since its discovery from Streptomyces
peucetius, they have been used to treat both solid and hematologic
malignancies 1. The most serious side effects of cardiotoxicity and
myelosuppression have limited their usage and dosing. Some proposed mechanisms
of cardiotoxicity involve direct pathways generating reactive oxygen species.

There are few cardioprotective measures that have been explored, but even these
treatments may not be enough from turning the patient to a cardiac patient.

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Doxorubicin is an effective chemotherapeutic agent used for
various cancers, and its major side effect is cardiotoxicity. Once doxorubicin
cardiomyopathy develops it carries a very poor prognosis. Often its effects can
be either acute occurring in 2-3 days after administration, or chronic
occurring years down the line. Initial manifestations are usually chest pain,
palpitations due to sinus tachycardia, paroxysmal nonsustained supraventricular
tachycardia. The ECG may reveal nonspecific ST-T changes and decreased
amplitude of QRS complexes 4. The incidence of cardiotoxicity is estimated to
be around 1.7%; however, the incidence increases with increased dosage of

The precise mechanism of how doxorubicin induces cardiotoxicity is
not fully understood. The accepted hypothesis is how anthracyclines interfere
with redox cycling in the mitochondria, which result in DNA damage due to
formation of reactive oxygen species (ROS) 5. These reactive oxygen species
can damage DNA, proteins, and breakdown lipid barriers, which often leads to
cellular death and myocyte death. However, recent study shows cardiomyocyte
damage first happens by drug interaction with a particular type of
topoisomerase, which is an enzyme that affects the DNA tension and formation
3. Topoisomerases induce breaks in the DNA, which allows regulation during
DNA replication, transcription, recombination and chromatin remodeling 6.  

The isoenzyme Top2 has two forms – Top2alpha and Top2 beta.

Top2alpha is more prevalent and is highly expressed in proliferating cells, and
it is important for chromosomal segregation. Top2beta is more abundant in
cardiomyocytes and its expression is constant throughout the cell cycle.

Doxorubicin exerts its effect by intercalating the DNA and binding with the
topoisomerase 2 isoenzymes forming a complex. When it is bound to Top2alpha, it
inhibits DNA replication and arrests the cell cycle in G1/G2 phase, and induces
apoptosis. When it is bound to Top2beta, it triggers a mitochondrial
dysfunction by suppressing receptors (PPAR) that help to regulate oxidative
metabolism. Without this regulation, this leads to an altered P53 tumor
suppressor pathway, beta-adrenergic signaling, impaired calcium handling, and
increased apoptosis 2.

Even though the exact mechanism of cardiotoxicity is not known, it
is crucial to identify the risk factors and perform a thorough history to make
the diagnosis. As stated earlier the incidence of cardiotoxicity increases with
cumulative dosing; which makes this the biggest risk factor. Other factors that
have been identified are extremes of age, female gender, radiation exposure, or
concomitant use with other anti-tumor agents 7. A complete cardiovascular
exam should be performed, assessing for elevated jugular venous pressure or an
S3 gallop; any signs of heart failure. An electrocardiogram should be obtained,
and most of the times for patients with cardiotoxicity there are usually some
nonspecific ST changes and low QRS complexes 4. An echocardiography with
Doppler studies is useful in detecting early diastolic and systolic LV
dysfunction. The history and physical exam will help in aiding the diagnosis,
however the gold standard for diagnosis is an endomyocardial biopsy of the
right ventricle. The tissue sample will show some histopathological changes
such as loss of myofibrils and distension of the sarcoplasmic reticulum and
T-tubules 8. After the biopsy is taken, it is scored on a scale from 1 to 5
based on the percentage of pathological changes. A score of 2.5 of greater is a
strong indicator that doxorubicin therapy should be ended. Since this is so
invasive, the diagnostic method is rarely used. Instead the physicians rely on
the history, physical and labs such as certain cardiac biomarkers. Since
doxorubicin causes cardiac myocyte injury, a useful marker to look to is
cardiac troponin T. Other markers include atrial-type and brain-type
natriuretic peptides. These peptides will be elevated when there is ventricular
dysfunction and heart failure.

Once the diagnosis of doxorubicin-cardiotoxicity is made there is
no specific treatment available. There are some methods to help manage the
problem of doxorubicin-induced heart failure. If there are signs of pulmonary
and systemic venous congestion, diuretics can be used to relieve the symptoms.

Use of an ACE inhibitor and beta-blocker to address ventricular dysfunction may
be appropriate as well. However, none of these treatments have demonstrated to
improve the prognosis of patients with doxorubicin-cardiotoxicity.

Lately, much of the emphasis has been on preventive measures. One
of the strategies is limiting to the cumulative dose of doxorubicin to <450 mg/m^2 4. Another avenue being explored is in the delivery of doxorubicin.

Delivering it in a PEGylated liposomal form will help to decrease the
free-floating doxorubicin, which results in selective uptake of the drug in
tumor cells.  Less free doxorubicin helps
to reduce oxidant stress 7. A drug that may help in cardioprotective measures
is carvedilol. This is a non-selective beta-antagonist with some antioxidant
activity. There have been some small studies of its protective effects in a
trial of non-metastatic breast cancer patients taking it as a monotherapy vs.

placebo, and another trial of children with acute lymphoblastic leukemia taking
carvedilol before their doxorubicin therapy. Both studies showed decreased
intervention while taking carvedilol 2. These measures have been useful in
small samples of patients, but an effective preventive therapy for
doxorubicin-cardiotoxicity have yet to be found.

Anthracyclines are an important class of drugs for treatment of
cancer, but their use is limited due to their cardiotoxic effects.

Doxorubicin’s toxicity is largely due to the generation of free radicals. These
radicals eventually result in ventricular dysfunction and heart failure. It is
important for patients with a clinical suspicion of toxicity to undergo close
monitoring. There are some strategies to reduce the cardiovascular effect of
doxorubicin such as lowered doses, PEGylated infusion of the drug, and
cardioprotective drugs such as carvedilol. Although these strategies have shown
some benefits against doxorubicin cardiotoxicity, more clinical investigation
into an effective prevention is needed. 


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