FDG-PET imaging for the evaluation of antiglioma agents in a rat model

Abstract

The increasing development of novel anticancer agents demands parallel advances in the methods used to rapidly assess their therapeutic efficacy (TE) in the preclinical phase. We evaluated the ability of small-animal PET, using the (18)F-fluoro-deoxy-D-glucose (FDG) radiotracer, to predict the TE of a number of anticancer agents in the rat C6 glioma model following 3 days of treatment. Semi-quantitative measurements of changes in FDG uptake during the course of treatment (standardized uptake value response [SUV(r)]) were found to be significantly lower in tumors treated with the hypoxia-inducible factor-1alpha inhibitor YC-1 (15 mg/kg) than in tumors in the control group. No significant SUV(r) change was observed following a similar 3-day regimen with the proapoptotic agent NS1619 (20 microg/kg), the combination of YC-1 and NS1619, or the alkylating agent temozolomide (7.5 mg/kg). Quantitative immunohistochemical studies demonstrated significantly lower levels of glucose transporter-1 (GLUT-1) expression in the YC-1-treated tumors, thereby correlating with the low SUV(r) observed in this group. The ability of SUV(r) to predict gold-standard outcomes of TE was further validated as YC-1-treated tumors had decreased volumes compared to control tumors. As such, we successfully demonstrated the ability of FDG-PET to rapidly determine the TE of novel agents for the treatment of glioma in the preclinical phase of evaluation.

Fig. 1

Standardized uptake value response (SUV_r) for each therapeutic group after 3 days of treatment. (A) SUV_r of each therapeutic group.*p < 0.05 compared with vehicle (control) group. (B) Representative coronal, axial, and sagittal ¹⁸F-fluorodeoxy-D-glucose PET images (left to right) of groups before and after treatment with dimethyl sulfoxide (DMSO) and YC-1. The scale bar represents relative percent activity. Abbreviations: TMZ, temozolomide; B, brain; T, tumor; HG, harderian gland.

Fig. 2

Molecular characterization of standardized uptake value response. (A) Representative Iba1, Ki-67, and GLUT-1 immunohistochemical (IHC) images of each therapeutic group. Images of GLUT-1 staining are shown from both invasive edges and necrotic regions of the tumors. (B – E) Quantification from IHC images: Iba1 (B), Ki-67 as the proliferation index (C), tumor cellularity (D), and GLUT-1 expression (E). *p < 0.05 compared with vehicle (control) group. Abbreviations: DMSO, dimethyl sulfoxide; TMZ, temozolomide; PI, proliferation index.

Fig. 3

Therapeutic efficacy of YC-1 in C6 glioma model. (A and B) Representative collagen IV immunohistochemical images (A) and quantitative analysis of collagen IV staining (B) for each therapeutic group. (C) Comparison of tumor volume after 7 days of treatment with YC-1 (n = 6) or dimethyl sulfoxide (DMSO) (n = 6). Vertical bars delineate minima and maxima of tumor volumes observed in each therapeutic group.*p < 0.05 compared with vehicle (control) group. Abbreviation: TMZ, temozolomide.