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 18F-FDG PET/CT

Purpose: Hypoxia-inducible factor 1a (HIF-1a) 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-1a expression improved the radiosensitivity of laryngeal carcinoma. We explored whether the expression of HIF-1a and GLUT-1 was correlated with 2 '-deoxy-2 '-[18F]fluoro-D-glucose (F-18-FDG) uptake and whether F-18-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 x 107/mL x 0.2 mL) and Tu212 cells (2 x 107/mL x 0.2 mL) into nude mice. The effects of HIF-1a antisense oligodeoxynucleotides (AS-ODNs) (100 mu g) and GLUT-1 AS-ODNs (100 mu g) 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 (23) design. F-18-FDG-PET/CT was taken before and after the treatment of xenografts. The relationships between HIF-1a and GLUT-1 expression and 18F-FDG uptake in xenografts were estimated and the value of F-18-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-1a 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 GLUT-1 and HIF-1a expression and therapeutic effect (necrosis, apoptosis). Conclusions: Simultaneous inhibition of HIF-1a and GLUT-1 expression might increase the radiosensitivity of laryngeal carcinoma, decreasing MVD, and promoting apoptosis and necrosis. F-18-FDG-PET/CT wasn't useful in evaluating the therapeutic effect on laryngeal cancer in this animal study.