title: Longitudinal evaluation of the metabolic response of a tumor xenograft model to single fraction radiation therapy using magnetic resonance spectroscopy.
abstract: Proton magnetic resonance spectroscopy (MRS) was used to evaluate the metabolic profile of human glioblastoma multiform brain tumors grown as xenografts in nude mice before, and at multiple time points after single fraction radiation therapy. Tumors were grown over the thigh in 16 mice in this study, of which 5 served as untreated controls and 11 had their tumors treated to 800 cGy with 200 kVp x-rays. Spectra were acquired within 24 h pre-treatment, and then at 3, 7 and 14 d post-treatment using a 9.4 T animal magnetic resonance (MR) system. For the untreated control tumors, spectra (1-2 per mouse) were acquired at different stages of tumor growth. Spectra were obtained with the PRESS pulse sequence using a 3  ×  3 × 3 mm(3) voxel. Analysis was performed with the LCModel software platform. Six metabolites were profiled for this analysis: alanine (Ala), myo-inositol (Ins), taurine (Tau), creatine and phosphocreatine (Cr + PCr), glutamine and glutamate (Glu + Gln), and total choline (glycerophosphocholine + phosphocholine) (GPC + PCh). For the treated cohort, most metabolite/water concentration ratios were found to decrease in the short term at 3 and 7 d post-treatment, followed by an increase at 14 d post-treatment toward pre-treatment values. The lowest concentrations were observed at 7 d post-treatment, with magnitudes (relative to pre-treatment concentration ratios) of: 0.42  ±  24.6% (Ala), 0.43  ±  15.3% (Ins), 0.68  ±  27.9% (Tau), 0.52  ±  14.6% (GPC+PCh), 0.49  ±  21.0% (Cr + PCr) and 0.78  ±  24.5% (Glu + Gln). Control animals did not demonstrate any significant correlation between tumor volume and metabolite concentration, indicating that the observed kinetics were the result of the therapeutic intervention. We have demonstrated the feasibility of using MRS to follow multiple metabolic markers over time for the purpose of evaluating therapeutic response of tumors to radiation therapy. This study provides supporting evidence that metabolite/water concentration ratios have the potential to be used as biomarkers for the assessment of the response to therapy.
authors.affiliation: Department of Medical Physics, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada.
authors.forename: A G
authors.initials: AG
authors.lastname: Tessier
authors.forename: A
authors.initials: A
authors.lastname: Yahya
authors.forename: M P
authors.initials: MP
authors.lastname: Larocque
authors.forename: B G
authors.initials: BG
authors.lastname: Fallone
authors.forename: A
authors.initials: A
authors.lastname: Syme
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002794:Choline / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D019583:Dose Fractionation, Radiation; D006801:Humans; D007294:Inositol / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D007294:Inositol; D003401:Creatine; D002794:Choline