A common chemotherapy drug could increase disease susceptibility in children of cancer survivors

A new study led by Washington State University researchers demonstrates that ifosfamide, a commonly-used chemotherapy drug, could have negative effects even on the children and grandchildren of cancer survivors who received chemotherapy during their adolescence, according to an institutional press release.

According to the results of a clinical trial, the offspring and grand-offspring of male rats who received ifosfamide during adolescence had higher disease susceptibility.

Previous research has already shown that cancer treatments could increase patients’ possibility of developing the disease later in life, but this study is significant for being one of the first-known research demonstrating susceptibility can be passed down to the third generation of unexposed offspring.

“The findings suggest that if a patient receives chemotherapy, and then later has children, that their grandchildren, and even great-grandchildren, may have an increased disease susceptibility due to their ancestors’ chemotherapy exposure,” said Michael Skinner, a biologist at Washington State University and corresponding author of the study.

However, Skinner also emphasized that chemotherapy can be a highly effective treatment, so these findings should not discourage cancer patients from receiving it.

As a precaution for cancer patients who plan to have children later, the researchers recommend considering cryopreservation to freeze germ cells before receiving chemotherapy.

Mimicking the course of a human patient's chemotherapy treatment

Chemotherapy is a cancer treatment that involves the use of medication to eradicate cancer cells. It comes in a wide variety of forms, but they all are designed to block cancer cells from multiplying, which stops them from developing and spreading in the body.

Ifosfamide, on the other hand, is a chemotherapy drug used to treat many types of cancer, such as testicular cancer, soft tissue sarcoma, osteosarcoma, bladder cancer, small cell lung cancer, cervical cancer, and ovarian cancer.

To mimic the course of treatment an adolescent human cancer patient would receive, researchers exposed young male rats to ifosfamide over three days and then bred them with female rats who were never exposed to the drug. The offspring were bred with other unexposed rats.

The results surprised researchers since not only the first generation but also the second generation had a great incidence of disease. Although there were some generational and sex-based variations, the rats have problems such as a greater incidence of kidney and testis diseases as well as delayed onset of puberty and abnormally low anxiety, indicating a lowered ability to assess risk.

A deeper understanding of the epigenetic shifts brought on by chemotherapy may also help patients understand their risk of developing specific diseases, opening the door to earlier prevention and treatment methods.

“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,” he said. “We could use epigenetics to help diagnose whether they’re going to have a susceptibility to disease.”

The results of the study were published in the journal iScience.

Study Abstract:

The current study was designed to use a rodent model to determine if exposure to the chemotherapy drug ifosfamide during puberty can induce altered phenotypes and disease in the grand-offspring of exposed individuals through epigenetic transgenerational inheritance. Pathologies such as delayed pubertal onset, kidney disease, and multiple pathologies were observed to be significantly more frequent in the F1 generation offspring of ifosfamide lineage females. The F2 generation grand-offspring ifosfamide lineage males had transgenerational pathology phenotypes of early pubertal onset and reduced testis pathology. Reduced levels of anxiety were observed in both males and females in the transgenerational F2 generation grand-offspring. Differential DNA methylated regions (DMRs) in chemotherapy lineage sperm in the F1 and F2 generations were identified. Therefore, chemotherapy exposure impacts pathology susceptibility in subsequent generations. Observations highlight the importance that prior to chemotherapy, individuals need to consider cryopreservation of germ cells as a precautionary measure if they have children.