Oligodendrocytes & precursors: toxicity of chemotherapy

描述（由申请人提供）：人们越来越认识到， 癌症治疗与严重的神经损伤有关，即使在 治疗中枢神经系统（CNS）以外癌症的患者。成像 研究揭示了在大脑中的各种异常， 化疗和越来越多的研究表明， 接受过以下治疗的患者中认知障碍的发生率较高 完全是化疗 我们认为，少突胶质细胞和CNS前体细胞的损伤提供了一个新的机制。 细胞基础，以了解不良的神经系统后果 用化疗剂治疗。我们发现 CNS的少突胶质细胞、神经胶质前体细胞和神经元前体细胞 易受广泛使用的化疗剂如BCNU和 顺铂，剂量在脑细胞正常 在癌症治疗期间暴露。许多化疗药物的性质 与进入大脑的准备好的催眠有关， 这些药物的外部，中枢神经系统的预期也可能与 神经毒性，这一假设得到了我们初步的体内实验的支持， BCNU的效果 我们的目标是详细了解化疗相关的 神经毒性，并开发选择性保护正常细胞免受 化疗的有害影响，而不损害这些效用， 细胞毒性剂杀死肿瘤细胞。我们将详细分析 使用体外和体内方法研究神经毒性。我们将提出两个 补充保护策略。第一种模式涉及监管 氧化剂平衡，一种已知的引发细胞凋亡的触发剂。第二 范例涉及抑制半胱天冬酶，死亡效应子的特定组分 途径。因此，我们将探索在体外和体内的方法来定义， 细胞群有被破坏或破坏的风险 化疗剂。此外，我们将确定和测试 选择性地保护正常细胞免受这种损伤， 在体外和体内保护癌细胞。

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.