Decreasing oxygen metabolism to redcue hypoxia and radiosensitize tumors.

描述(申请人提供)：50多年来，肿瘤缺氧一直被认为是成功放射治疗的障碍。然而，通过向肿瘤输送更多氧气来克服这一障碍的尝试在临床上一直令人失望，这主要是由于肿瘤血管系统的功能限制。这项应用不是通过增加氧气输送来减少缺氧，而是通过减少肿瘤内的氧气消耗来限制缺氧。如果提供给肿瘤的氧气供应是恒定的，那么短暂的需求减少将增加整体功能氧合。常用的抗糖尿病药物(二甲双胍、苯双胍)在体外至少部分通过抑制电子传递链(ETC)复合体1而降低线粒体的功能。我们建议验证这一假说，即药物下调线粒体代谢将减少细胞对氧气的需求，导致肿瘤缺氧减少和模型肿瘤的特异性放射增敏。这种方法在使用低分割放射方案时尤其有效，因为在这种方案中，氧气增强可以对整体肿瘤细胞的杀伤产生深远的影响。我们将这一提议组织成以下四个具体目标。1)确定肿瘤抑制基因LKB1在双胍对线粒体代谢影响中的作用。2)确定葡萄糖和谷氨酰胺作为线粒体燃料在调节线粒体对双胍干预反应中的相对重要性。3)定量研究双胍类化合物对体内线粒体功能、肿瘤缺氧和葡萄糖消耗的生化影响。4)建立皮下和原位模型肿瘤放射增敏的最佳水平。值得注意的是，由于正常组织通常有良好的氧合，这种全身治疗方法将特异性地使肿瘤放射增敏，而不会导致正常组织毒性增加。

DESCRIPTION (provided by applicant): Tumor hypoxia has been recognized as a hindrance to successful radiation therapy for over 50 years. Attempts to overcome this obstacle by delivering more oxygen to the tumor, however, have been clinically disappointing, largely due to the functional limitations of the tumor vasculature. Instead of reducing hypoxia by increased delivery of oxygen, this application proposes to limit hypoxia by reducing oxygen consumption within the tumor. If the supply of oxygen delivered to the tumor is constant, then transient reduction in demand will increase overall functional oxygenation. Commonly prescribed anti-diabetic biguanidedrugs (metformin, phenformin) have been shown to reduce mitochondrial function in vitro at least in part through inhibition of electron transport chain (ETC) complex 1. We propose to test the hypothesis that pharmacologic downregulation of mitochondrial metabolism will reduce cellular demand for oxygen and result in decreased tumor hypoxia and specific radiosensitization of model tumors. This approach will be especially effective when using hypofractionated radiation protocols where oxygen enhancement can have a profound effect on overall tumor cell killing. We have organized this proposal into the following four specific aims. 1) Determine the role of tumor suppressor LKB1 in mediating the effect of biguanides on mitochondrial metabolism. 2) Establish the relative importance of glucose versus glutamine as a mitochondrial fuel in regulating mitochondrial response to intervention with biguanides. 3) Quantitate the biochemical effect of biguanides on mitochondrial function, tumor hypoxia, and glucose consumption in vivo. And 4) Establish the optimal level of radiosensitization in both subcutaneous and orthotopic model tumors treated with biguanides and radiation. It is important to note that because normal tissue is typically well oxygenated, thi systemic approach will specifically radiosensitize tumors, without causing enhanced normal tissue toxicity.