GLUTAMINE AND BREAST CANCER PROLIFERATION AND TREATMENT

谷氨酰胺是一种生长和维持的必需营养物质 哺乳动物细胞在培养中，肿瘤细胞是贪婪的谷氨酰胺 消费者。然而，人们对其致病机制知之甚少。 谷氨酰胺支持肿瘤细胞的增殖和存活。此修订版 应用程序将测试谷氨酰胺提供的总体假设 具有还原等价物的肿瘤细胞及其前体 谷胱甘肽合成，这是一种对细胞至关重要的分子 防止化学和氧化损伤。谷氨酰胺利用 可能有助于细胞的氧化还原代谢及其机制 细胞对氧化和异物应激做出反应。 一系列表现出广泛谷氨酰胺的人类乳腺细胞系 依赖于增长和生存能力，以及广泛的 谷氨酰胺利用率，已经确定。此外， 两种对谷氨酰胺高度敏感的乳腺细胞株对 谷氨酰胺饥饿已被表征，并将直接用于 检验一些假设：1)谷氨酰胺被用来提供谷氨酸 和用于合成谷胱甘肽的半胱氨酸。2)谷氨酰胺利用率 提供肿瘤细胞线粒体的还原等价物，因此 通过线粒体氧化还原控制肿瘤细胞生长和存活 机械装置。3)靶向抑制谷氨酰胺酶表达，第一 参与谷氨酰胺分解的酶，抑制谷氨酰胺的利用 从而抑制生长并增加肿瘤细胞对 用谷胱甘肽解毒的化疗药物。总体而言, 将开发阻断肿瘤细胞使用谷氨酰胺的方法， 以及这种策略在抑制肿瘤生长或治疗方面的有效性 增加肿瘤对化疗药物的敏感性将是 检查过了。这可能为新陈代谢导向的研究提供基础。 癌症疗法。

Glutamine is an essential nutrient for the growth and maintenance of mammalian cells in culture, and tumor cells are avid glutamine consumers. However, little is known about the mechanism by which glutamine supports tumor cell proliferation and viability. This revised application will test the overall hypothesis that glutamine provides tumor cells with reductive equivalents as well as precursors for glutathione synthesis, a molecule which is essential for cellular protection against chemical and oxidative damage. Glutamine utilization may contribute to cellular redox metabolism and the mechanism by which cells respond to oxidative and xenobiotic stress. A series of human breast cell lines exhibiting a wide range of glutamine dependence for growth and viability, as well as a wide range of glutamine utilization rates, have been identified. In addition, the response of two highly glutamine-sensitive breast cell lines to glutamine starvation has been characterized and will be used to directly test a number of hypotheses: 1) Glutamine is-used to provide glutamate and cystine for synthesis of glutathione. 2) Glutamine utilization provides reductive equivalents to tumor cell mitochondria and therefore controls tumor cell growth and viability through mitochondrial redox mechanisms. 3) Targeted inhibition of glutaminase expression, the first enzyme involved in glutaminolysis, represses glutamine utilization and thereby inhibits growth and increases the sensitivity of tumor cells to chemotherapeutic drugs which are detoxified by glutathione. In general, methods to block the use of glutamine by tumor cells will be developed, and the efficacy of this strategy for inhibiting tumor growth or for increasing the sensitivity of tumors to chemotoxic drugs will be examined. This may provide the basis for novel metabolically directed cancer therapies.