Chemotherapy for elimination of malignancies kills cells. Chemotherapeutic drugs, however, cannot differentiate abnormal vs. normal cells. There is still much work to be done to create chemotherapeutic drugs which kill only sick cells. Until that time, cancer patients just tolerate some noxious side effects from chemotherapy harming healthy cells because the stakes are high – often life and death.
Not all side effects of anti-malignancy drugs are identified, understood, preventable, reversible, or trivial. “Chemo brain” is a common term used by cancer survivors to describe thinking and memory problems that can occur during and after chemical cancer treatment. Chemo brain can also be called chemo fog, cancer-related cognitive impairment, or cognitive dysfunction.
Up to 75 percent of patients receiving cancer chemotherapy suffer from chemo brain — a long-term side effect that interferes with memory, consistent attention, and learning. Children can experience chemo brain when their brains are still developing. The academic and emotional fall out can be life-altering.
“When we meet with parents and talk about the life-saving therapy we are proposing for their child’s cancer, one of the most distressing potential side effects we sometimes describe is cognitive loss,” says pediatric oncologist Dr. Lisa Diller, chief medical officer for the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, in a statement. “If we had preventive treatments that could be delivered during therapy, or later in the survivorship phase of care, that would be a game changer.”
Maria Lehtinen, PhD and Naama Kanarek, PhD, both with the Department of Pathology at Boston Children’s Hospital, are collaborating to investigate chemo brain and its mitigation. They envision treating the cerebrospinal fluid (CSF) that bathes the brain and spinal cord to protect the brain from the toxic effects of chemotherapy.
Kanarek has been studying the metabolic effects of the chemotherapy drug methotrexate on cancer cells. Methotrexate is used in children for numerous malignancies. Some of these include acute lymphoblastic leukemia that has spread to the brain, osteosarcoma, and some tumors of the central nervous system. In adults, it is used to treat leukemia, lymphoma, breast cancer, and lung cancer.
Lehtinen and Kanarek first studied mice. They determined that methotrexate caused a metabolic imbalance leading to the production of toxic oxygen molecules. It damaged the CSF, the choroid plexus, and nerve cells in the hippocampus — the brain’s most active center of learning and memory. The mice showed increased anxiety and impairment on tasks involving short-term learning and memory.
The scientists discovered that methotrexate inhibited the choroid plexus from secreting a key, antioxidant enzyme, superoxide dismutase 3 (SOD3). SOD3 protects cells in the brain and other tissues by breaking down potentially toxic oxygen molecules. Without SOD3 delivered by the CSF, brain cells are vulnerable to harm.
The nextstep was investigation with human tissue. The researchers studied human neurons generated from stem cells. With methotrexate, they produced less SOD and showed oxidative damage.
Next, they studied CSF samples from 11 adults who had received methotrexate for lymphomas affecting their central nervous system. These patients had reduced levels of SOD3 in their CSF and evidence of oxidative damage.
To determine if adding SOD3 could protect the brain, the scientists used gene therapy in mice to boost SOD3 production in the choroid plexus. Examination after methotrexate was administered showed that the CSF and brain tissue were largely free of oxidative damage. The mice showed less anxiety and memory impairment.
Future projects will explore the effects of other chemotherapy drugs on the CSF and choroid plexus. The team also plans to better define how methotrexate and antioxidants affect the brain, and to test the efficacy of antioxidants given directly.
Antioxidant treatments could be administered intravenously, as a nasal spray, or directly into the CSF by spinal tap. Such treatments could possibly be given together with the chemotherapy. An immediate opportunity might be in patients who are using methotrexate for brain cancer, or for leukemia or lymphoma with brain involvement, says Kanarek.
Another potential approach is consuming antioxidants through foods or dietary supplements.
“This first study is just the tip of the iceberg,” says Lehtinen. “If we could correct the collateral damage of chemotherapy and make even a small improvement in the trajectory of patients’ lives, that would be really exciting.”
This study is published in Neuron, 6 September 2022.