Overhauser Enhanced Magnetic Resonance Imaging (OMRI)

1) 3-溴丙酮酸作为抗代谢物治疗荷瘤小鼠的作用抗代谢物3-溴丙酮酸已被证明通过关闭线粒体的能量产生而具有抗肿瘤作用。早期的报道表明，这对肿瘤缺氧区域也有效。我们通过pO2定位和13C成像进行了系统的研究，发现3-溴丙酮酸的疗效取决于单羧酸转运蛋白-1 （MCT-1）的表达。这是首次使用13C丙酮酸进行连续pO2成像和代谢成像。2)胰腺肿瘤异种移植物的肿瘤缺氧和有氧糖酵解。我们研究了三种不同的胰腺肿瘤细胞表型作为异种移植物在小鼠体内的pO2状态和糖酵解效率，并进一步研究了它们在体内的放射反应。三种肿瘤细胞系分别为Miapaca、HS766T和Su8686。按pO2计算的pO2状态为SU8686&gt；Miapaca>HS766T。与Warburg效应一致的糖酵解效率为：HS766T&gt；MiaPaca>Su8686。肿瘤pO2状态与体内糖酵解活性的相关性研究尚属首次。有了这三种胰腺肿瘤细胞表型的肿瘤pO2状态的先验知识，我们随后评估了体内的放射反应。放射反应表明肿瘤pO2是治疗反应的关键决定因素。结果表明，Su 86.86反应最灵敏，HS766T反应最小，Miapaca反应居中。我们还发现，丙酮酸作为大剂量给药可增强缺氧细胞毒素TH-302对Hs766T和Miapaca的疗效，但对Su8686没有作用。3)肿瘤pO2和糖酵解活性序贯成像。我们使用EPRI对荷瘤小鼠的pO2进行序贯EPR成像，使用13C丙酮酸作为示踪剂使用代谢MRI对糖酵解活性进行序贯EPR成像，并观察放射治疗后这些特性的变化。我们发现，在3gy照射后，缺氧比例立即增加，但24小时后出现肿瘤再氧合。本研究将指导分级放疗计划，利用肿瘤pO2增高的时间窗。

1) Effect of 3-bromopyruvate as ant-metabolite in treating tumor bearing miceThe anti-metabolite 3-bromopyruvate has been shown to be having anti-tumor effects by shutting down the energy production in the mitochondria. Earlier reports suggest that this is efficacious in hypoxic regions in the tumor as well. We conducted a systematic investigation using pO2 mapping and 13C imaging and found that the efficacy of 3-Bromopyruvate depends on the expression of monocarboxylate transporter-1 (MCT-1). This is the first demonstration of serial pO2 imaging and metabolic imaging using 13C pyruvate. 2) Tumor hypoxia and aerobic glycolysis of pancreatic tumor xenografts.We have examined three different pancreatic tumor cell phenotypes as xenografts in mice for their pO2 status and glycolytic erfficiency and further examine their radioresponse in vivo. The three tumor cell lines tested were Miapaca, HS766T, and Su8686. The pO2 status in terms of pO2 was SU8686>Miapaca>HS766T. The glycolytic efficiency, consistent with Warburg effect was as follows: HS766T>MiaPaca>Su8686. Such correlative studies between tumor pO2 status and glycolytic activity in vivo are being demonstrated for the first time. With a priori knowledge of tumor pO2 status of these three pancreatic tumor cell phenotypes, we then evaluated the radioresponse in vivo. The radiation response showed that tumor pO2 is a crucial determinant in response to therapy. We found that Su 86.86 to be the most responsive and HS766T to be the least and Miapaca to be intermediate. We also found that pyruvate administration as a bolus dose enhanced the efficacy of a hypoxic cytotoxin TH-302 in Hs766T and Miapaca but not in Su8686. 3) Sequential imaging of tumor pO2 and glycolytic activity.We are conducting sequential EPR imaging of tumor bearing mice for tumor pO2 using EPRI and glycolytic activity using metabolic MRI using 13C pyruvate as a tracer and looking at changes in these properties after radiation treatment. We find that immediately after a 3 Gy exposure, the hypoxic fraction increases but 24 hours later there is a tumor reoxygenation. This study will provide guidance to schedule fractionated radiotherapy to make use of temporal window of increased tumor pO2.