Common drugs used to treat cancer may be more harmful to healthy brain cells than the cancer cells that they are intended to destroy. That is the conclusion of a study conducted by researchers at the University of Rochester Medical Center and published today in the Journal of Biology. The results, which also indicate that chemotherapy may cause long-term brain damage, represent the closest that scientists have come to pinpointing the underlying physiological cause of "chemo brain," a common side effect of cancer treatment that scientists are only now beginning to comprehend.
Cancer patients who receive chemotherapy have long complained of adverse neurological side effects ranging from memory loss to, in extreme cases, seizures, vision loss and even dementia. Until very recently, these conditions were often dismissed as unrelated to the cancer treatment and rather the result of the patient's mental state. However, a growing body of evidence has documented the scope and cognitive impact of chemo brain. A study earlier this year conducted by the James P. Wilmot Cancer Center at the University of Rochester suggested that upwards of 82% of cancer patients reported that they suffer from some form of cognitive impairment.
While scientists have suspected that chemotherapy may have an impact on healthy cells in the central nervous system, the precise mechanisms of this condition were not fully understood. Now a University of Rochester team led by Mark Noble, Ph.D. believes that they have unraveled the mystery behind chemo brain. "This is the first study that puts chemo brain on a sound scientific footing, in terms of neurobiology and cellular biology."
As in other organs and systems in the body, the central nervous system is populated with several types of cells that produce or repair the cells needed for normal function. These cells fall into three general categories: dividing stem cells, dividing intermediate cells types called precursors and progenitors, and non-dividing mature cells.
Noble and his team exposed several different populations of healthy brain cells as well as multiple human cancer cell lines to clinically relevant levels of three commonly used chemotherapy drugs – carmustine, cisplatin, and cytosine arabinoside. These drugs are used to treat a wide range of cancers, including certain types of breast cancer, lung cancer, colon cancer, leukemia, Hodgkin and non-Hodgkin lymphomas, and, in the case of carmustine, brain tumors.
They discovered that these drugs were far more toxic to the healthy brain cells than to cancer cells; exposure levels typically used when treating patients killed 70-100% of neural cells but just 40-80% of the cancer cells. In animal models, several types of healthy cells continued to die for at least six weeks after treatment. Notably, these drugs were toxic to both non-dividing cells and dividing stem cells, precursors, and progenitors even at very low concentrations. Destruction of dividing cells was not altogether unexpected, as that is what these drugs are designed to target. However, the loss of dividing cells has onerous consequences as these populations are responsible for replenishing the other cell types in the central nervous system.
Noble speculates that there are two possible ways the destruction of these healthy cells result in cognitive problems. First, scientists believe that the cell division – or neurogenesis – that occurs in the hippocampus is essential to learning and memory. Hence, the cognitive side effects of chemotherapy could potentially be traced to the drugs' disruption of the process of neurogenesis in this particular region of the brain.
Noble also points to the destruction of a specific cell type that plays a critical supporting role in the central nervous system. These cells, called oligodendrocytes, are responsible for producing myelin, the fatty substance that, like insulation wrapped around a wire, covers nearly all the large nerve cells processes – called axons – in our bodies and helps signals in the nervous system move crisply and rapidly from one point to another.
"The oligodendrocyte is an amazing cell that from its cell body supports a volume of myelin membrane that can be thousands of times the volume of the cell body," says Noble. "Myelin membranes are very dynamic and are always being turned over and renewed. However, if you kill the oligodendrocyte cell, then myelin membrane eventually disintegrates."
Because everything in the nervous system is based upon precise timing of information transfer, this destruction of the insulation necessary in normal impulse transmission has significant neurological ramifications.
Noble and his team are quick to point out that no one should avoid cancer treatment because of these results and that chemotherapy will remain a cornerstone of cancer therapy for the foreseeable future. Instead, they believe that the opportunity for the scientific community is to use this knowledge to develop ways to protect the brain's cells from these drugs. Their research points to several potential strategies that the Rochester scientists are now pursuing, ranging from application of protective agents to understanding why some people are spared neurological side effects while others are not. Additionally, the approach used in the study could serve as a screening method to analyze the effectiveness of new cancer therapies to determine, in advance, which cell populations are at risk during treatment.
Funding for the research came from the National Institutes of Health and the James P. Wilmot Cancer Foundation. Other investigators participating in the study were Joerg Dietrich, M.D, Ph.D., formerly of the University of Rochester and now currently affiliated with Harvard University, and Ruolan Han, Ph.D., Yin Yang Ph.D., and Margot Mayer-Proschel, Ph.D., all with the University of Rochester.
Journal
Journal of Biology