Assessment of treatment response by autoradiography with (14)C-aminocyclopentane carboxylic acid, (67)Ga-DTPA, and (18)F-FDG in a herpes simplex virus thymidine kinase/ganciclovir brain tumor model.
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 (18)F-FDG, (67)Ga-diethylenetriaminepentaacetic acid ((67)Ga-DTPA), and (14)C-aminocyclopentane carboxylic acid ((14)C-ACPC) were obtained; measurements of (14)C-ACPC and (67)Ga-DTPA plasma clearance (K(1)), (14)C-ACPC transport ( partial differential K(1)), 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 partial differential K(1) and % dose/g of (14)C-ACPC in RG2TK+ xenografts to approximately 30% of that in nontreated animals (from 34 +/- 9 [mean +/- SD] to 9.5 +/- 2.7 microL/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.


CONCLUSIONS
(14)C-ACPC influx, K(1)(ACPC), facilitated transport, partial differential K(1)(ACPC), and % dose/g (ACPC) are good indicators of early treatment response after HSV-tk/GCV gene therapy. The parametric images and changes in K(1)(ACPC), partial differential K(1)(ACPC), 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 (67)Ga-DTPA and (18)F-FDG. Amino acid transport imaging may be a good surrogate paradigm to monitor treatment response of brain tumors.
Miyagawa
Tadashi
T
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Oku
Takamitsu
T
Sasajima
Toshio
T
Dasai
Rovathi
R
Beattie
Bradley
B
Finn
Ronald
R
Tjuvajev
Juri Gelovani
JG
Blasberg
Ronald
R
D000818:Animals; D001345:Autoradiography; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D003515:Cycloleucine / Q000378:metabolism*; D019788:Fluorodeoxyglucose F18; D005710:Gallium Radioisotopes; D015774:Ganciclovir / Q000494:pharmacology*; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D004369:Pentetic Acid / Q000378:metabolism*; D011877:Radionuclide Imaging; D051381:Rats; D011916:Rats, Inbred F344; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*
D005710:Gallium Radioisotopes; D003515:Cycloleucine; D019788:Fluorodeoxyglucose F18; D004369:Pentetic Acid; D013937:Thymidine Kinase; D015774:Ganciclovir