CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo.
CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo.
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作者：
Dietrich J;Han R;Yang Y;Mayer-Pröschel M;Noble M
癌症患者的化疗可能伴随严重的短期和长期的神经不良反应，如白质脑病和认知障碍，即使是全身治疗。这些不良反应的潜在细胞基础尚不清楚。我们发现，三种主流化疗药物——卡莫司定（BCNU）、顺铂和阿糖胞苷（阿糖胞苷），分别代表两种DNA交联剂和一种抗代谢物，在临床相关暴露水平下应用于培养细胞，对中枢神经系统祖细胞和非分裂少突胶质细胞的毒性大于对多种癌细胞系的毒性。在体外和体内观察到细胞死亡增强和细胞分裂抑制。在小鼠全身给药时，这些化疗药物与心室下区、海马齿状回和中枢神经系统胼胝体的细胞死亡增加和细胞分裂减少有关。在某些情况下，在药物服用结束后的几周内，细胞分裂减少，细胞死亡增加。在任何癌症治疗过程中，识别处于危险中的神经群对于开发减少神经毒性和保持长期幸存者生活质量的方法都具有重要意义。因此，除了为全身化疗对神经系统的不良影响提供可能的解释外，体外和体内分析之间的强相关性表明，我们用于识别报告毒性的相同方法也可以为分析新疗法和发现实现选择性保护或靶向杀伤的方法提供快速的体外筛选。
Chemotherapy in cancer patients can be associated with serious short- and long-term adverse neurological effects, such as leukoencephalopathy and cognitive impairment, even when therapy is delivered systemically. The underlying cellular basis for these adverse effects is poorly understood. We found that three mainstream chemotherapeutic agents – carmustine (BCNU), cisplatin, and cytosine arabinoside (cytarabine), representing two DNA cross-linking agents and an antimetabolite, respectively – applied at clinically relevant exposure levels to cultured cells are more toxic for the progenitor cells of the CNS and for nondividing oligodendrocytes than they are for multiple cancer cell lines. Enhancement of cell death and suppression of cell division were seen in vitro and in vivo. When administered systemically in mice, these chemotherapeutic agents were associated with increased cell death and decreased cell division in the subventricular zone, in the dentate gyrus of the hippocampus and in the corpus callosum of the CNS. In some cases, cell division was reduced, and cell death increased, for weeks after drug administration ended. Identifying neural populations at risk during any cancer treatment is of great importance in developing means of reducing neurotoxicity and preserving quality of life in long-term survivors. Thus, as well as providing possible explanations for the adverse neurological effects of systemic chemotherapy, the strong correlations between our in vitro and in vivo analyses indicate that the same approaches we used to identify the reported toxicities can also provide rapid in vitro screens for analyzing new therapies and discovering means of achieving selective protection or targeted killing.