Role of Mitochondria and Glycolysis in Tumor Cell MDR

说明：大多数癌症化疗药物用于临床靶点 位于实体瘤外层的快速分裂细胞。在……里面 相比之下，位置更靠中央的细胞以厌氧代谢 难以治疗，因为它们的生长速度较慢。因此，它们会显示一个表单 对多种抗癌药的多重耐药性。厌氧菌， 然而，它为干扰的试剂提供了一个自然的选择性窗口 糖酵解，这是本应用程序的中心主题。通过这件事 我们打算获得信息，以刺激癌症的新倡议 利用生长缓慢的过敏症进行化疗 无氧代谢肿瘤细胞，用糖酵解抑制剂治疗其 最终在病人身上使用。已经开发出三种不同的肿瘤细胞模型 来研究这一自然现象，所有人似乎都对 糖酵解抑制剂。细胞模型A代表一次治疗后的肿瘤细胞 罗丹明123，专用于解偶联电子上的ATP合成 运输；细胞模型B是P0细胞丢失了线粒体DNA和 因此不能进行氧化磷酸化；细胞Mc表示肿瘤 细胞在厌氧环境中，通过暴露在低氧条件下 (氮气)或以球体的形式给予它们。我们的初步数据表明 细胞模型A和B对已知的2-脱氧核糖核酸抑制剂超敏 糖酵解。此外，细胞模型A的体内数据表明， 肿瘤是可以的，将在这里得到确认和进一步探索。品种繁多 不同形式的多药耐药的肿瘤细胞类型将被用于 求婚。这里将使用多种不同的技术，其中包括： 克隆存活率、生长抑制试验、乳酸分析、球体 培养，线粒体呼吸测定，荧光显微镜，高效液相和 人异种移植小鼠。此外，糖酵解的新抑制剂将是 在我们的三个细胞模型中合成并测试。更多系列简单阳离子 定位于线粒体的化合物将被用来探索如何：(A) Bl线粒体功能导致肿瘤细胞对 糖酵解抑制剂和(B)它们如何选择性地杀死白血病细胞。 我们的长期目标是将糖酵解抑制剂与标准 化疗，通过选择性地杀死厌氧菌来增强其疗效， 生长缓慢的肿瘤细胞发现实体瘤的内核，通常是 最具抵抗力，因此也是最难根除的。

DESCRIPTION: Most cancer chemotherapeutic agents used in the clinic target rapidly-dividing cells which are found n the outer layers of solid tumors. In contrast, the more centrally located cells, which metabolize anaerobically difficult to treat because of their slower growth. Hence, they display a form of multidrug resistance to a wide range anti-cancer agents. Anaerobiosis, however, provides a natural window of selectivity for agents which interfere glycolysis, which is the central theme of this application. Through this proposal we intend to obtain information to stimulate new initiatives in cancer chemotherapy to exploit the hypersensitivity of slow-grow anaerobic-metabolizing tumor cells, with inhibitors of glycolysis for their eventual use in patients. Three distinct tumor cell models have been developed to examine this natural phenomenon and all appear to be hypersensitive to glycolytic inhibitors. Cell Model A represents tumor cells treated at a d rhodamine 123 which specifically uncouples ATP synthesis from electron transport; Cell Model B are p0 cells have lost their mitochondrial DNA and therefore cannot undergo oxidative phosphorylation; and Cell Mc denotes tumor cells in an anaerobic environment, either by exposure to hypoxic conditions (nitrogen) or by giving them as spheroids. Our preliminary data suggest that Cell Models A & B are hypersensitive to 2-deoxyglu known inhibitor of glycolysis. Moreover, in vivo data with cell model A, indicate that cures of tumors can be ac which will be confirmed and further explored here. A variety of tumor cell types, with different forms of MDR, will be used in this proposal. A number of diverse techniques will be employed here which include: clonogenic survival, growth inhibitory assays, lactic analysis, spheroid culture, mitochondrial respiratory assays, fluorescence microscopy, HPLC and human xenograph mice. In addition, new inhibitors of glycolysis will be synthesized and tested in our three cell models. More series of simple cationic compounds which localize in mitochondria, will be utilized to explore how: (a) bl mitochondrial function leads to hypersensitization of tumor cells to glycolytic inhibitors and (b) how they may selectively kill leukemic cells. Our long-term goal is to use glycolytic inhibitors, in conjunction with standard chemotherapy, to enhance its efficacy by selectively killing the anaerobic, slow-growing tumor cells found inner core of solid tumors which are usually the most resistant and consequently the most difficult to eradicate.