Cancer treatments cause many different side effects. These often limit dosing and adversely affect patients’ quality of life. In some cases, they are serious, require treatment, and can be life threatening. In most cases, the side effects of cancer therapy resolve over time, but in some cases, they are permanent. An example of this is the permanent heart damage caused by a class of chemotherapeutic drugs known as the anthracyclines. These include drugs such as doxorubicin, daunorubicin, and Doxil®. Anthracyclines inhibit the synthesis of genetic material and block the action of key DNA enzymes like topoisomerase II. They are the cornerstone drugs in treating various cancers such as leukemia, lymphoma, and breast cancer. Unfortunately, anthracyclines cause cardiac injury resulting in cardiomyopathy, the loss of heart function. The cardiotoxicity of anthracyclines is dose-dependent -- the degree of cardiac injury depends on the drug dose that the patient receives. Once doctors detect signs of cardiotoxicity, they adjust the dose of anthracyclines or find an alternative, often less effective, drug. Because the heart damage associated with the anthracyclines is permanent, even if cardiomyopathy is not detected during cancer treatment, patients are limited to a lifetime dose on the order of one gram for an average adult. And even at this limited dose, 25% of patients experience noticeable heart deficiency within 2 years of treatment. Sometimes cardiotoxic side effects can go undetected for years following cancer treatment. Long-term cardiovascular complications may develop in cancer survivors. For example, according to the American Heart Association, breast cancer survivors in the US now have a higher risk of dying from heart disease than from cancer. Over the years, researchers and physicians have attempted many approaches to reducing the cardiotoxicity of cancer therapy. Many have involved redesigning anthracycline drugs to engineer out the cardiotoxicity while preserving the chemotherapeutic benefit of the drugs. Others involve drug targeting using “magic bullets’ such as monoclonal antibodies and nanoparticles. Doxil encapsulates the anthracycline drug in lipid spheres known as liposomes to improve absorption of the drug in tumors. Unfortunately, to date, none of these has shown significant benefit in reducing the cardiotoxicity of therapy while maintaining the efficacy of the cancer treatment. Other approaches involve developing entirely new drugs to treat the cancer. For example, scientists have developed targeted cancer therapies intended to boost therapeutic effectiveness while limiting side effects. Yet many targeted therapies, including HER2 inhibitors, still result in heart disease. Trastuzumab is an antibody targeting HER2 receptors in breast cancer. Many clinical trials reveal that trastuzumab also causes a significant decline in cardiac function in cancer patients.

1. Combating Chemotherapy-Induced Cardiotoxicity
Brian Frenzel

2. Introduction
Cancer treatments cause many different side effects. These often limit dosing and
adversely affect patients’ quality of life. In some cases, they are serious, require
treatment, and can be life threatening. In most cases, the side effects of cancer
therapy resolve over time, but in some cases, they are permanent.

3. An example of this is the permanent heart damage caused by a class of
chemotherapeutic drugs known as the anthracyclines. These include drugs such as
doxorubicin, daunorubicin, and Doxil®.

4. Anthracyclines inhibit the synthesis of genetic material and block the action of key
DNA enzymes like topoisomerase II. They are the cornerstone drugs in treating
various cancers such as leukemia, lymphoma, and breast cancer.

5. Unfortunately, anthracyclines cause cardiac injury resulting in cardiomyopathy, the
loss of heart function. The cardiotoxicity of anthracyclines is dose-dependent -- the
degree of cardiac injury depends on the drug dose that the patient receives. Once
doctors detect signs of cardiotoxicity, they adjust the dose of anthracyclines or find an
alternative, often less effective, drug. Because the heart damage associated with the
anthracyclines is permanent, even if cardiomyopathy is not detected during cancer
treatment, patients are limited to a lifetime dose on the order of one gram for an
average adult. And even at this limited dose, 25% of patients experience noticeable
heart deficiency within 2 years of treatment.

6. Sometimes cardiotoxic side effects can go undetected for years following cancer
treatment. Long-term cardiovascular complications may develop in cancer survivors.
For example, according to the American Heart Association, breast cancer survivors in
the US now have a higher risk of dying from heart disease than from cancer.

7. Over the years, researchers and physicians have attempted many approaches to
reducing the cardiotoxicity of cancer therapy. Many have involved redesigning
anthracycline drugs to engineer out the cardiotoxicity while preserving the
chemotherapeutic benefit of the drugs. Others involve drug targeting using “magic
bullets’ such as monoclonal antibodies and nanoparticles. Doxil encapsulates the
anthracycline drug in lipid spheres known as liposomes to improve absorption of the
drug in tumors. Unfortunately, to date, none of these has shown significant benefit in
reducing the cardiotoxicity of therapy while maintaining the efficacy of the cancer
treatment.

8. Other approaches involve developing entirely new drugs to treat the cancer. For
example, scientists have developed targeted cancer therapies intended to boost
therapeutic effectiveness while limiting side effects. Yet many targeted therapies,
including HER2 inhibitors, still result in heart disease. Trastuzumab is an antibody
targeting HER2 receptors in breast cancer. Many clinical trials reveal that
trastuzumab also causes a significant decline in cardiac function in cancer patients.

9. Tosk, Inc., a California-based biotechnology company specializing in drugs to prevent
the side effects of cancer therapies, has developed a product called TK-39, which
blocks the cardiotoxic effects of the anthracyclines as well as trastuzumab. The
company’s research studies show that administration of TK-39 results in lower
production of troponin I, a marker of cardiac damage, and improves the heart
pumping capacity of animals receiving high doses of chemotherapy. Tosk is
completing the final stages of preclinical testing before submitting TK-39 for
approval by the Food and Drug Administration (FDA).

10. Until such products are fully integrated into clinical practice, professional
organizations have established recommendations for cancer patients at risk of
chemotherapy-induced cardiotoxicity. For instance, the American Society of
Echocardiography and the European Association of Cardiovascular Imaging
recommend that doctors perform a thorough echocardiographic assessment of
patients’ cardiovascular function before starting chemotherapy.

11. Based on their findings, doctors can tailor the chemotherapy regimen and dosage to
limit the likelihood of cardiotoxicity or reduce its severity. Further, recommendations
also cover on-therapy and post-therapy evaluations to address long-term
cardiovascular complications.