The central nervous system toxicity of metabolic chemotherapy.

摘要

Chemotherapy in cancer patients can be associated with serious short and long-term neurological adverse effects, such as leukoencephalopathy and cognitive impairment. The underlying cellular basis for these adverse effects is poorly understood. We have found that two widely used anti-metabolic chemotherapeutic agents - cytosine arabinoside (Ara-C) and 5-fluorouracil (5-FU) - were even more toxic for progenitor cells of the CNS and non-dividing oligodendrocytes than they are for multiple cancer cell lines. Moreover, at sub-lethal doses these agents compromised the capacity of progenitor cells for continued cell division. We also found these agents could increase the intracellular ROS production of progenitor cells even at low doses, and that the antioxidant NAC attenuated the adverse effects of these agents on the progenitor cells and oligodendrocytes. When administered systemically, both chemotherapeutic agents were associated with increased cell death and decreased cell division in several regions of the CNS, often with effects that lasted for weeks or even months after drug administration. Confocal analysis using cell-type specific makers revealed that the affected cell populations were mostly CNS precursor cells and oligodendrocytes, which was consistent with the predictions made from the in vitro observation. Moreover, systemically administered 5-FU induced acute CNS damages including vasculature apoptosis, blood-brain-barrier permeablization and inflammation. 5-FU treatment also caused a delayed demyelination syndrome reminiscent of multifocal leukoencephalopathy. Auditory brainstem responses of 5-FU treated mice revealed functional impairment parallel to the pathological changes. These findings provide a potential cellular basis for understanding adverse neurological consequences following chemotherapy, and thus identifying targets for preventing or alleviating such damage. This study also describes the first known animal model for the delayed leukoencephalopathy following chemotherapy, and thus providing tools for further investigation of the mechanisms of such poorly understood phenomena and for development of protection strategies.