Oligodendrocytes & precursors: toxicity of chemotherapy

描述(申请人提供)：越来越多的人认识到 癌症治疗与严重的神经损伤有关，即使在 接受中枢神经系统(CNS)外癌症治疗的患者。成象 研究揭示了大脑在以下方面的各种异常 化疗和越来越多的研究表明令人不安的是 接受药物治疗的患者认知功能障碍的频率较高 完全是化疗。 我们认为对少突胶质细胞和CNS前体细胞的损伤提供了一种 了解阿司匹林不良神经后果的细胞学基础 用化疗药物治疗。我们发现， 中枢神经的少突胶质细胞、神经胶质前体细胞和神经元前体细胞 容易受到广泛使用的化疗药物的影响，如BCNU和 顺铂，剂量完全在脑细胞正常范围内 在癌症治疗期间暴露。许多化疗药物的性质 与大脑的通透性有关，所以给药 在这些药物之外，中枢神经系统的可能也与 神经毒性，这一假说得到了我们初步的体内实验的支持 BCNU的作用。 我们的目标是发展对化疗相关疾病的详细了解 神经毒性和开发选择性保护正常细胞的方法 化疗的有害影响而不影响这些的效用 杀灭肿瘤细胞的细胞毒剂。我们将制定一项详细的分析 使用体外和体内方法的神经毒性。我们将提出两个建议 互补的保护策略。第一个范式涉及监管 氧化剂平衡，已知的启动细胞凋亡的触发器。第二 范式涉及抑制半胱氨酸酶，死亡效应器的特定成分 小路。因此，我们将探索体外和体内的方法来确定 细胞种群有可能被破坏或摧毁 化疗药物。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害，而不是同时 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.