Role of Mitochondria and Glycolysis in Tumor Cell MDR

描述：临床上使用的大多数癌症化疗药物的靶点 在实体瘤的外层发现的快速分裂的细胞。在 相比之下，位于更中心的细胞，其厌氧代谢 因为它们生长缓慢，所以很难治疗。因此，它们显示一种形式 对多种抗癌药物的多药耐药性。厌氧生活， 然而，这为干扰剂提供了一个天然的选择性窗口， 糖酵解，这是这个应用程序的中心主题。通过这个 我们打算获得信息，以刺激癌症的新举措 化疗以利用生长缓慢的 厌氧代谢肿瘤细胞，糖酵解抑制剂， 最终用于患者。已经开发了三种不同的肿瘤细胞模型 研究这种自然现象，所有人似乎都对 糖酵解抑制剂细胞模型A代表在第二天处理的肿瘤细胞。 罗丹明123特异性地将ATP合成与电子 转运;细胞模型B是p0细胞已经失去了它们的线粒体DNA， 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，或者通过暴露于缺氧条件， （氮）或通过将它们作为球状体给予。我们的初步数据显示， 细胞模型A和B对2-脱氧葡萄糖的已知抑制剂过敏。 糖酵解此外，细胞模型A的体内数据表明， 肿瘤可以是AC，这将在这里得到证实和进一步探讨。各种 肿瘤细胞类型，具有不同形式的MDR，将用于本研究。 提议这里将采用一些不同的技术，其中包括： 克隆形成存活，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，HPLC和 人类异种移植小鼠。此外，新的糖酵解抑制剂将 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 定位于线粒体中的化合物将用于探索如何：（a） BL线粒体功能导致肿瘤细胞对 糖酵解抑制剂和（B）它们如何选择性杀死白血病细胞。 我们的长期目标是使用糖酵解抑制剂，与标准的 化疗，通过选择性地杀死厌氧菌， 缓慢生长的肿瘤细胞发现实体瘤的内核，通常是 最具抵抗力，因此最难根除。

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.