PT  - JOURNAL ARTICLE
AU  - Tadashi Miyagawa
AU  - Takamitsu Oku
AU  - Toshio Sasajima
AU  - Rovathi Dasai
AU  - Bradley Beattie
AU  - Ronald Finn
AU  - Juri Gelovani Tjuvajev
AU  - Ronald Blasberg
TI  - Assessment of Treatment Response by Autoradiography with <sup>14</sup>C-Aminocyclopentane Carboxylic Acid, <sup>67</sup>Ga-DTPA, and <sup>18</sup>F-FDG in a Herpes Simplex Virus Thymidine Kinase/Ganciclovir Brain Tumor Model
DP  - 2003 Nov 01
TA  - Journal of Nuclear Medicine
PG  - 1845--1854
VI  - 44
IP  - 11
4099  - http://jnm.snmjournals.org/content/44/11/1845.short
4100  - http://jnm.snmjournals.org/content/44/11/1845.full
SO  - J Nucl Med2003 Nov 01; 44
AB  - Assessments of herpes simplex virus 1 thymidine kinase (HSV-tk)/ganciclovir (GCV) treatment response, early in the course of therapy, are important in the evaluation and clinical management of patients. This study addresses whether imaging amino acid transport, glucose utilization, and passive vascular permeability provides an early indication of treatment response and can predict long-term outcome. Methods: Fischer 344 rats with intracerebral HSV-tk transduced RG2TK+ xenografts were studied. GCV-treated (50 mg/kg twice daily) and saline-treated control animals were compared; triple-label quantitative autoradiography was performed 3 d after initiating treatment, and long-term survival was determined. Autoradiograms of 18F-FDG, 67Ga-diethylenetriaminepentaacetic acid (67Ga-DTPA), and 14C-aminocyclopentane carboxylic acid (14C-ACPC) were obtained; measurements of 14C-ACPC and 67Ga-DTPA plasma clearance (K1), 14C-ACPC transport (∂K1), relative glucose utililization (R), and normalized radioactivity (% dose/g) were obtained in tumor and brain tissues. Adjacent sections were stained to detect apoptotic cells, microvessels, and type L neutral amino acid transporter in tumor and normal brain. Results: GCV treatment reduced ∂K1 and % dose/g of 14C-ACPC in RG2TK+ xenografts to ∼30% of that in nontreated animals (from 34 ± 9 [mean ± SD] to 9.5 ± 2.7 μL/min/g and from 0.28 ± 0.09 to 0.11 ± 0.04 % dose/g, respectively). GCV had a significant but substantially smaller effect than toxicity on glucose utilization and little or no effect on passive vascular permeability of RG2TK+ xenografts. These differences could not be explained by differences in plasma amino acid or glucose concentration at the time of the study. Histology revealed a large fraction of dead tumor cells and only a sparse distribution of apoptotic cells in GCV-treated tumors. Many CD34-positive endothelial cells in GCV-treated tumors showed only weak or marginal LAT1 staining, whereas CD98 staining remained unchanged. Survival was significantly increased by GCV treatment from 18 ± 4 to 56 ± 17 d. Conclusion: 14C-ACPC influx, K1ACPC, facilitated transport, ∂K1ACPC, and % dose/g ACPC are good indicators of early treatment response after HSV-tk/GCV gene therapy. The parametric images and changes in K1ACPC, ∂K1ACPC, and % dose/g ACPC are substantial and are better than the corresponding measures obtained in the same animals and in the same tissue (tumor) regions with 67Ga-DTPA and 18F-FDG. Amino acid transport imaging may be a good surrogate paradigm to monitor treatment response of brain tumors.