Oligodendrocytes & precursors: toxicity of chemotherapy

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DESCRIPTION (provided by applicant): There is an increasing recognition that cancer treatment is associated with serious neurological impairment, even in patients treated for cancers outside the central nervous system (CNS). Imaging studies are revealing a variety of abnormalities in the brain following chemotherapy and an increasing number of studies demonstrate a disturbingly high frequency of cognitive impairment in patients who have received exclusively chemotherapy. We propose that damage to oligodendrocytes and CNS precursor cells provides a cellular basis for understanding the adverse neurological consequences of treatment with chemotherapeutic agents. We have discovered that oligodendrocytes, glial precursor cells and neuronal precursor cells of the CNS are vulnerable to widely used chemotherapeutic agents, such as BCNU and cisplatin, at doses well within the range to which brain cells would normally be exposed during cancer treatment. The nature of many chemotherapeutic agents is associated with a ready penetrance into the brain, such that administration of these drugs outside, of the CNS might be expected also to be associated with neurotoxicity, a hypothesis supported by our preliminary in vivo experiments on the effects of BCNU. Our goals are to develop a detailed understanding of chemotherapy-associated neurotoxicity and to develop means of selectively protecting normal cells from the harmful effects of chemotherapy without compromising the utility of these cytotoxic agents in killing tumor cells. We will develop a detailed analysis of neurotoxicity using in vitro and in vivo approaches. We will propose two complementary protective strategies. The first paradigm involves regulation of oxidant balance, a known trigger for initiation of apoptosis. The second paradigm involves inhibition of caspases, specific components of death effector pathways. Thus, we will explore in vitro and in vivo approaches to define cellular populations at risk from being damaged or destroyed by chemotherapeutic agents. In addition, we will identify and test means of selectively protecting normal cells from such damage without simultaneously protecting cancer cells in vitro as well as in vivo.