Decreasing oxygen metabolism to redcue hypoxia and radiosensitize tumors.

描述（由申请人提供）：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令人失望，这主要是由于肿瘤脉管系统的功能限制。代替通过增加氧的递送来减少缺氧，本申请提出通过减少肿瘤内的氧消耗来限制缺氧。如果输送到肿瘤的氧气供应是恒定的，那么需求的短暂减少将增加整体功能性氧合。已证明常用的抗糖尿病双胍类药物（二甲双胍、苯丙氨酸）至少部分通过抑制电子传递链（ETC）复合物1在体外降低线粒体功能。我们建议测试的假设，药理学下调线粒体代谢将减少细胞对氧的需求，并导致减少肿瘤缺氧和特定的放射增敏模型肿瘤。当使用大分割放射方案时，这种方法将特别有效，其中氧增强可以对整体肿瘤细胞杀伤产生深远影响。我们将这一建议分为以下四个具体目标。1)确定肿瘤抑制因子LKB 1在介导双胍类药物对线粒体代谢的影响中的作用。2)确定葡萄糖与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)定量双胍类对线粒体功能、肿瘤缺氧和体内葡萄糖消耗的生化作用。和4）在用双胍和放射治疗的皮下和原位模型肿瘤中建立放射增敏的最佳水平。重要的是要注意，因为正常组织通常氧合良好，所以这种全身方法将特异性地使肿瘤放射增敏，而不引起增强的正常组织毒性。

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.