"Facilitated" amino acid transport is upregulated in brain tumors Journal Article
| Authors: | Miyagawa, T.; Oku, T.; Uehara, H.; Desai, R.; Beattie, B.; Tjuvajev, J.; Blasberg, R. G. |
| Article Title: | "Facilitated" amino acid transport is upregulated in brain tumors |
| Abstract: | The goal of this study was to determine the magnitude of 'facilitated' amino acid transport across tumor and brain capillaries and to evaluate whether amino acid transporter expression is 'upregulated' in tumor vessels compared to capillaries in contralateral brain tissue. Aminocyclopentane carboxylic acid (ACPC), a non-metabolized [14C]-labeled amino acid, and a reference molecule for passive vascular permeability, [67Ga]-gallium- diethylenetriaminepentaacetic acid (Ga-DTPA), were used in these studies. Two experimental rat gliomas were studied (C6 and RG2). Brain tissue was rapidly processed for double label quantitative autoradiography 10 minutes after intravenous injection of ACPC and Ga-DTPA. Parametric images of blood-to- brain transport (K1(ACPC) and K1(Ga-DTPA), μL/min/g) produced from the autoradiograms and the histology were obtained from the same tissue section. These three images were registered in an image array processor; regions of interest in tumor and contralateral brain were defined on morphologic criteria (histology) and were transferred to the autoradiographic images to obtain mean values. The facilitated component of ACPC transport (δK1(ACPC)) was calculated from the K1(ACPC) and K1(Ga-DTPA) data, and paired comparisons between tumor and contralateral brain were performed. ACPC flux, K1(ACPC), across normal brain capillaries (22.6 ± 8.1 μL/g/min) was >200- fold greater than that of Ga-DTPA (0.09 ± 0.04 μL/g/min), and this difference was largely (~90%) due to facilitated ACPC transport. Substantially higher K1(ACPC) values compared to corresponding K1(DTPA) values were also measured in C6 and RG2 gliomas. The δK1(ACPC) values for C6 glioma were more than twice that of contralateral brain cortex. K1(ACPC) and δK1(ACPC) values for RG2 gliomas was not significantly higher than that of contralateral cortex, although a ~2-fold difference in facilitated transport is obtained after normalization for differences in capillary surface area between RG2 tumors and contralateral cortex. K1(ACPC), δK1(ACPC), and K1(DTPA) were directly related to tumor cell density, were higher in regions of 'impending' necrosis, and the tumor/contralateral brain ACPC radio-activity ratios (0 to 10 minutes) were very similar to that obtained with 0 to 60 minutes experiments. These results indicate that facilitated transport of ACPC is upregulated across C6 and RG2 glioma capillaries, and that tumors can induce upregulation of amino acid transporter expression in their supporting vasculature. They also suggest that early imaging (e.g., 0 to 20 minutes) with radiolabeled amino acids in a clinical setting may be optimal for defining brain tumors. |
| Keywords: | controlled study; carrier protein; nonhuman; brain tumor; glioma; brain neoplasms; animal cell; animals; animal experiment; animal model; neovascularization, pathologic; glioma cell; rat; blood brain barrier; blood-brain barrier; neoplasms, experimental; amino acid; rats; cell density; amino acids; image processing; tumor vascularization; radioisotopes; cerebrovascular circulation; biological transport; gallium 67; autoradiography; amino acid transport; facilitation; rats, inbred f344; pentetic acid; blood vessel permeability; brain capillary; quantitative autoradiography; cycloleucine; male; priority journal; article; facilitated transport; aminocyclopentane carboxylic acid; diethylenetriaminepentaacetic acid; transporter expression |
| Journal Title: | Journal of Cerebral Blood Flow and Metabolism |
| Volume: | 18 |
| Issue: | 5 |
| ISSN: | 0271-678X |
| Publisher: | Sage Publications Ltd. |
| Date Published: | 1998-05-01 |
| Start Page: | 500 |
| End Page: | 509 |
| Language: | English |
| PUBMED: | 9591842 |
| PROVIDER: | scopus |
| DOI: | 10.1097/00004647-199805000-00005 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 12 December 2016 -- Source: Scopus |
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