Drugs used to treat cancer may damage normal, healthy brain cells more than the cancer cells they are meant to target. A study published today in the open access journal Journal of Biology shows that clinical doses of chemotherapeutic drugs used to treat many common cancers cause long-term damage to the brains of mice by killing neural stem cells and oligodendrocytes, which produce the myelin insulation needed for normal neuronal function, and by impairing neural stem cell division. These results might explain the adverse neurological side effects - including reduction in cognitive abilities - observed in some cancer patients treated with chemotherapy. The approach used in the current study could also provide a rapid screening method to analyse new therapies and identify cell populations at risk during cancer treatment.
Joerg Dietrich and colleagues working in the group of Mark Noble, from the University of Rochester in the USA, exposed human neural stem cells, oligodendrocyte precursor cells and neuron-restricted precursor cells, in culture, to three chemotherapeutic agents: cisplatin, carmustine and cytarabine. Dietrich et al. also exposed different human cancer cell lines, such as uterine, breast or colon cancer cell lines to the same chemotherapeutic agents. Cisplatin is used to treat a wide range of cancers, including breast cancer, lung cancer and colon cancer and carmustine is used to treat brain tumours, Hodgkin and non-Hodgkin lymphomas. Both agents act by modifying the structure of DNA. Cytarabine, which interferes with cell metabolism, is used to treat leukaemia and lymphomas.
Dietrich et al.’s results show that clinical concentrations of cisplatin, carmustine and cytarabine are more toxic to human neural cells than to cancer cells. The drugs are toxic to both the dividing neural stem cells and the non-dividing cells such as astrocytes and neurons, even at very low concentrations. Results show that exposure to low micromolar concentrations of cisplatin, carmustine or cytarabine causes a 60-90% reduction in the viability of oligodendrocyte precursor cells and neuron precursor cells, but has little effect on most of the cancer cell lines examined. The authors show that to kill 40-80% of cancer cells, doses that also kill 70-100% of neural cells are required.
Using live mice treated with each of the drugs, Dietrich et al. show that cells of the nervous system of the mice continue to die for at least six weeks after the end of treatment. The drugs kill both dividing stem cells and non-dividing precursor cells of the nervous system in live mice. They also cause long-lasting reductions in cell division and proliferation in the central nervous system of the mice.
CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo
Joerg Dietrich, Ruolan Han, Yin Yang, Margot Mayer-Pröschel and Mark Noble
Journal of Biology 2006, 5:22 (30 November 2006)
Journal of Biology