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.
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