Can The ‘Red Devil’ Be Tamed?

By Steve Blanchard - July 12, 2020

For decades, the chemotherapy drug doxorubicin has been part of the arsenal in treating patients with several forms of cancer, including breast cancer and leukemia. The potent drug is a part of a class of compounds known as anthracyclines and is used to treat an estimated one million cancer patients each year.

While it’s a powerful drug, it’s also very toxic. That and its red hue has given it the unflattering nickname the “Red Devil.” It’s known to punish the cardiac system while it treats cancer, a dangerous side effect.

But research suggests that there may be a way to reduce the drug’s toxicity without blunting its ability to attack tumors. An academic team in the Netherlands plans to test two potentially safer versions of doxorubicin’s drug class in people.

According to Dr. Roohi Ismail-Khan, a medical oncologist who serves as the co-director of Moffitt Cancer Center’s Cardio-Oncology Program, a safer form of the drug called Doxil is already used to treat various cancers, especially gynecologic and breast cancers. This drug has a liposomal delivery, meaning it is inside tiny fat particles making it easier for the body to absorb with fewer side effects.

“The field of cardio-oncology was originally based on the significant cardiac side effects breast cancer patients had when trastuzumab was added to anthracyclines,” Ismail-Khan said. Although this combination improved survival in breast cancer patients, it also increased the risk of cardiac toxicity. “We encourage all patients treated with anthracyclines to follow up in the cardiac survivorship program if they would like to continue monitoring.”

Ismail-Khan said that patients are also encouraged to meet with a cardio-oncologist if they have pre-existing heart disease and are going to be treated with this class of drugs, or any cardio-toxic drugs for that matter.

“That will help us mitigate both short term and long term cardiac side effects,” she said.

Anthracyclines, the class of compounds that includes doxorubicin, were originally extracted from streptomyces bacteria. They have antibiotic properties but also proved to be some of the most potent chemotherapies ever found. But because of the damage they can bring to the heart, physicians often avoid giving them to elderly patients.

In addition, many childhood cancers are treated with high doses of the drugs, but cardiac problems sometimes haunt survivors later in life, along with a risk of new tumors, which doctors have attributed to DNA damage from the drug.

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"It’s important to remember, even if successful, it usually takes 10 years for a drug to get through clinical trials and become a viable FDA-approved option."

- Dr. Roohi Ismail-Khan, medical oncologist

This new research hoping to detoxify the drug is not the first to attempt to do so. Researchers have tried to reduce the heart risks by, for example, packaging the drugs in fat so they will home in on tumors, with limited success. But chemist Jacques Neefjes and his team at Leiden University and collaborators tried a different approach based on a surprising finding about how the drugs fight cancer, which they and a separate U.S. group reported in 2013.

Science Magazine explains that drugs kill rapidly dividing cells, such as those in a tumor, by blocking an enzyme they need to untangle and repair DNA as they replicate. But the researchers found doxorubicin also kills cancer cells by dislodging histones, the spherical proteins that DNA coils around like a spool to form a structure known as chromatin. This chromatin damage appears to interfere with the transcription of genes into proteins and other cell processes.

In the new research from the Netherlands, the team tested two anthracycline variants that remove histones without breaking DNA and created a new cancer drug called aclarubicin and another tweaked version of doxorubicin they call diMe-Doxo.

The researchers found the compounds worked as well as the original drug at killing cultured cancer cells and were nearly as effective at slowing tumor growth in mice. Yet mice prone to developing tumors that were dosed with aclarubicin did not show signs of heart damage, suggesting people treated with the drugs might be spared these effects.

There is also evidence that those treated with the new drugs were less likely to develop tumors later, according to a report published in the June Proceedings of the National Academy of Sciences.

But what does all of this mean for cancer patients?

“The drugs we’ve discussed will have to go through clinical trials to see if they are just as efficacious without the cardiac toxicity,” Ismail-Khan said. “If these drugs can show non-inferiority in trials, this would offer a viable option for patients who otherwise could not tolerate anthracycline-based therapy. But it’s important to remember, even if successful, it usually takes 10 years for a drug to get through clinical trials and become a viable FDA-approved option.”

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