In vivo evaluation of the effects of simultaneous inhibition of GLUT-1 and HIF-1α by antisense oligodeoxynucleotides on the radiosensitivity of laryngeal carcinoma using micro 18 F-FDG PET/CT

// Li-Fang Shen 1 , Xin Zhao 2 , Shui-Hong Zhou 1 , Zhong-Jie Lu 3 , Kui Zhao 2 , Jun Fan 4 , Min-Li Zhou 1 1 Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, China 2 Center of PET/CT, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, China 3 Department of Radiotherapy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, China 4 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, China Correspondence to: Shui-Hong Zhou, email: zhouyunzhoush@163.com Keywords: hypoxia-inducible factor 1α, glucose transporter-1, antisense oligodeoxynucleotides, radiosensitivity, 18 F-FDG micro PET/CT Received: November 04, 2016      Accepted: March 15, 2017      Published: March 29, 2017 ABSTRACT Purpose: Hypoxia-inducible factor 1α (HIF-1α) and glucose transporter-1 (GLUT-1) are two important hypoxic markers associated with the radioresistance of cancers including laryngeal carcinoma. We evaluated whether the simultaneous inhibition of GLUT-1 and HIF-1α expression improved the radiosensitivity of laryngeal carcinoma. We explored whether the expression of HIF-1α and GLUT-1 was correlated with 2′-deoxy-2’-[18F]fluoro-D-glucose ( 18 F-FDG) uptake and whether 18 F-FDG positron emission tomography-computed tomography (PET/CT) was appropriate for early evaluation of the response of laryngeal carcinoma to targeted treatment in vivo . Materials and Methods: To verify the above hypotheses, an in vivo model was applied by subcutaneously injecting Hep-2 (2 × 107/mL × 0.2 mL) and Tu212 cells (2 × 107/mL × 0.2 mL) into nude mice. The effects of HIF-1α antisense oligodeoxynucleotides (AS-ODNs) (100 μg) and GLUT-1 AS-ODNs (100 μg) on the radiosensitivity of laryngeal carcinoma were assessed by tumor volume and weight, microvessel density (MVD), apoptosis index (AI) and necrosis in vivo based on a full factorial (2 3 ) design. 18 F-FDG-PET/CT was taken before and after the treatment of xenografts. The relationships between HIF-1α and GLUT-1 expression and 18 F-FDG uptake in xenografts were estimated and the value of 18 F-FDG-PET/CT was assessed after treating the xenografts. Results: 10 Gy X-ray irradiation decreased the weight of Hep-2 xenografts 8 and 12 days after treatment, and the weights of Tu212 xenografts 8 days after treatment. GLUT-1 AS-ODNs decreased the weight of Tu212 xenografts 12 days after treatment. There was a synergistic interaction among the three treatments (GLUT-1 AS-ODNs, HIF-1α AS-ODNs and 10Gy X-ray irradiation) in increasing apoptosis, decreasing MVD, and increasing necrosis in Hep-2 xenografts 8 days after treatment ( p < 0.05) and in Tu212 xenografts 12 days after treatment ( p < 0.001). Standardized uptake value (tumor/normal tissue)( SUVmaxT/N) did not show a statistically significant correlation with GLUT1 and HIF-1α expression and therapeutic effect (necrosis, apoptosis). Conclusions: Simultaneous inhibition of HIF-1α and GLUT-1 expression might increase the radiosensitivity of laryngeal carcinoma, decreasing MVD, and promoting apoptosis and necrosis. 18 F-FDG-PET/CT wasn’t useful in evaluating the therapeutic effect on laryngeal cancer in this animal study.