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.
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