Proliferation-dependent changes in amino acid transport and glucose metabolism in glioma cell lines.

Amino acid imaging is increasingly being used for assessment of brain tumor malignancy, extent of disease, and prognosis. This study explores the relationship between proliferative activity, amino acid transport, and glucose metabolism in three glioma cell lines (U87, Hs683, C6) at different phases of growth in culture. Growth phase was characterized by direct cell counting, proliferation index determined by flow cytometry, and [(3)H]thymidine (TdR) accumulation, and was compared with the uptake of two non-metabolized amino acids ([(14)C]aminocyclopentane carboxylic acid (ACPC) and [(14)C]aminoisobutyric acid (AIB)), and [(18)F]fluorodeoxyglucose (FDG). Highly significant relationships between cell number (density), proliferation index, and TdR accumulation rate were observed in all cell lines ( r>0.99). Influx ( K(1)) of both ACPC and AIB was directly related to cell density, and inversely related to the proliferation index and TdR accumulation in all cell lines. The volume of distribution ( V(d)) for ACPC and AIB was lowest during rapid growth and highest during the near-plateau growth phase in all cell lines. FDG accumulation in Hs683 and C6 cells was unaffected by proliferation rate, growth phase, and cell density, whereas FDG accumulation was correlated with TdR accumulation, growth phase, and cell density in U87 cells. This study demonstrates that proliferation rate and glucose metabolism are not necessarily co-related in all glioma cell lines. The values of K(1) and V(d) for ACPC and AIB under different growth conditions suggest that these tumor cell lines can up-regulate amino acid transporters in their cell membranes when their growth conditions become adverse and less than optimal.

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.

UNLABELLED: 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. CONCLUSION: (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.