Early Assessment of the Efficacy of Temozolomide Chemotherapy in Experimental Glioblastoma Using [18F]FLT-PET Imaging

Thomas Viel,Andreas H Jacobs,Katrin Schwegmann,Stefan Wagner,Cornelius Faber,Sonja Schelhaas,Klaus Kopka,Michael Schäfers,Michael Kuhlmann,Lydia Wachsmuth,Juri G Gelovani

doi:10.1371/journal.pone.0067911

Abstract

Addition of temozolomide (TMZ) to radiation therapy is the standard treatment for patients with glioblastoma (GBM). However, there is uncertainty regarding the effectiveness of TMZ. Considering the rapid evolution of the disease, methods to assess TMZ efficacy early during treatment would be of great benefit. Our aim was to monitor early effects of TMZ in a mouse model of GBM using positron emission tomography (PET) with 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT).MethodsHuman glioma cells sensitive to TMZ (Gli36dEGFR-1) were treated with sub-lethal doses of TMZ to obtain cells with lower sensitivity to TMZ (Gli36dEGFR-2), as measured by growth and clonogenic assays. Gli36dEGFR-1 and Gli36dEGFR-2 cells were subcutaneously (s.c.) or intracranially (i.c.) xenografted into nude mice. Mice were treated for 7 days with daily injection of 25 or 50 mg/kg TMZ. Treatment efficacy was measured using [18F]FLT-PET before treatment and after 2 days. Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) were used to determine tumor volumes before treatment and after 7 days.ResultsA significant difference was observed between TMZ and DMSO treated tumors in terms of variations of [18F]FLT T/B ratio as soon as day 2 in the i.c. as well as in the s.c. mouse model. Variations of [18F]FLT T/B uptake ratio between days 0 and 2 correlated with variations of tumor size between days 0 and 7 (s.c. model: ntumor = 17 in nmice = 11, P<0.01; i.c. model: ntumor/mice = 9, P<0.01).ConclusionsOur results indicate that [18F]FLT-PET may be useful for an early evaluation of the response of GBM to TMZ chemotherapy in patients with glioma.

Highlights

Primary malignant central nervous system tumors represent about 2% of all cancers and account for a high rate of morbidity and mortality
Our results indicate that [18F]FLT-positron emission tomography (PET) may be useful for an early evaluation of the response of GBM to TMZ chemotherapy in patients with glioma
Resection followed by combined radiotherapy and temozolomide (TMZ) chemotherapy is the standard therapy protocol for patients suffering from GBM [3,4,5]

Summary

Introduction

Primary malignant central nervous system tumors represent about 2% of all cancers and account for a high rate of morbidity and mortality. They are the leading cause of death from solid tumors in children and the third leading cause of death from cancer in adolescents and adults aged 15 to 34 years [1]. Overexpression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), which antagonizes the genotoxic effects of alkylating agents like TMZ, is recognized as an unfavorable prognostic marker of the efficacy of alkylating chemotherapy [6], [7]. Factors other than MGMT expression may be involved in TMZ resistance, such as overexpression of the mismatch repair system or attenuation of wildtype p53 function [8]

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