The ‘hereditary’ toxicity of chemotherapy

The effectiveness of chemotherapy could be debated all day. But what it comes down to is this…

If diagnosed with cancer, any one of us would most likely opt for it. Right now, the medical community doesn’t have much else to offer us.

There is radiation and immunotherapy. Both of these are often done in tandem with chemotherapy, depending on the type of cancer.

But here’s the dilemma: chemotherapy is toxic. That toxicity is sort of a necessary evil to kill cancer cells, but that’s not all it does.

Cardiotoxicity is an example. This is what happens when chemotherapy impairs heart function and structure or accelerates the development of cardiovascular disease. Along with radiation and some immunotherapies, cardiovascular side effects, including high blood pressure, abnormal heart rhythms and heart failure can worsen.

It also does a number on the immune system.

But if you’re weighing surviving cancer against the toxic effects of the therapy — well, you can see why so many go through with it. And why so many look for alternative cancer therapies.

But what if you had to weigh its toxic effects on your future children?

Toxicity of chemotherapy impacts offspring’s health

Most of us have worried about the hereditary risks for developing cancers associated with close family members, especially our parents.

But research into the field of epigenetics reveals that chemotherapy may pose a “hereditary” risk that can be passed onto the children and grandchildren of cancer patients.

While prior research has shown that cancer treatments can increase patients’ chances of developing disease later in life, a Washington State University study is one of the first to show the risks from another angle.

Ifosfamide is a common chemotherapy drug that may be used alone or in combination with other drugs to treat many different types of cancer, among them some types of testicular cancers, ovarian cancer, lymphoma, sarcoma and lung cancer. It’s administered via IV (oral administration resulted in severe neurotoxicity) usually along with a neuroprotective compound.

Its mechanism of action is to bind to DNA, cause cell damage that leads to apoptosis (cell death) and upregulate reactive oxygen species (ROS), also known as free radicals, ultimately resulting in irreparable DNA damage.

In their study, WSU researchers exposed young male rats to ifosfamide over three days, a course of treatment that mimics what an adolescent human cancer patient might receive.

These exposed rats were later bred with female rats who had not been exposed to the drug. The resulting offspring were bred again with another set of unexposed rats.

The results were disturbing. Not only did the offspring of the exposed rats experience greater incidence of certain diseases, but their offspring did as well.

An epigenetic inheritance

The “children” and “grandchildren” of the exposed rats had a greater incidence of disease of the kidneys and testes, as well as delayed onset of puberty.

They also demonstrated abnormally low anxiety, meaning that they lacked an adequate ability to assess and avoid risk.

The researchers analyzed the rats’ epigenomes. These are molecular processes that operate independently to influence how genes are expressed, including turning genes on or off.

It became apparent that the negative effects of ifosfamide were the epigenetic inheritance of the offspring rats. In other words, they were affected not because they’d been exposed to the drug, but because their gene expression had been altered.

Hope for the future

Michael Skinner, a WSU biologist and corresponding author on the study, stressed that the findings shouldn’t dissuade patients from chemotherapy treatment since, in his words, it can be effective.

But he suggests that young adults take precautions if they plan on having children later in life. He recommends considering cryopreservation, or the freezing of sperm or egg cells, prior to undergoing treatment.

And, for the children and grandchildren of chemotherapy patients, continuing research holds hope of informing them of their likelihood of developing certain diseases, so they can take early preventive measures.

“We could potentially determine if a person’s exposure had these epigenetic shifts that could direct what diseases they’re going to develop, and what they’re going to potentially pass on to their grandchildren,” Skinner says. “We could use epigenetics to help diagnose whether they’re going to have a susceptibility to disease.”

Sources:

Chemotherapy could increase disease susceptibility in future generations Eureka Alert

Examination of generational impacts of adolescent chemotherapy: Ifosfamide and potential for epigenetic transgenerational inheritance iScience

Ifosfamide — National Library of Medicine