FACILITATED AMINO-ACID-TRANSPORT IS UP-REGULATED IN BRAIN-TUMORS

The goal of this study was to determine the magnitude of ''facilitated '' amino acid transport across tumor and brain capillaries and to eval uate whether amino acid transporter expression is ''upregulated'' in t umor vessels compared to capillaries in contralateral brain tissue. Am inocyclopentane carboxylic acid (ACPC), a non-metabolized [C-14]-label ed amino acid, and a reference molecule for passive vascular permeabil ity, [Ga-67]-gallium-diethylenetriaminepentaacetic acid (Ga-DTPA), wer e used in these studies. Two experimental rat gliomas were studied (C6 and RG2). Brain tissue was rapidly processed for double label quantit ative autoradiography 10 minutes after intravenous injection of ACPC a nd Ga-DTPA. Parametric images of blood-to-brain transport (K-1(ACPC) a nd K-1(Ga-DTPA), mu L/min/g) produced from the autoradiograms and the histology were obtained from the same tissue section. These three imag es were registered in an image array processor; regions of interest in tumor and contralateral brain were defined on morphologic criteria (h istology) and were transferred to the autoradiographic images to obtai n mean values. The facilitated component of ACPC transport (partial de rivative K-1(ACPC)) was calculated from the K-1(ACPC) and K-1(Ga-DTPA) data, and paired comparisons between tumor and contralateral brain we re performed. ACPC flux, K-1(ACPC), across normal brain capillaries (2 2.6 +/- 8.1 mu L/g/min) was >200-fold greater than that of Ga-DTPA (0. 09 +/- 0.04 mu L/g/min), and this difference was largely (similar to 9 0%) due to facilitated ACPC transport. Substantially higher K-1(ACPC) values compared to corresponding K-1(DTPA) values were also measured i n C6 and RG2 gliomas. The partial derivative K-1(ACPC) values for C6 g lioma were more than twice that of contralateral brain cortex, K-1(ACP C) and partial derivative K-1(ACPC) values for RG2 gliomas was not sig nificantly higher than that of contralateral cortex, although a simila r to 2-fold difference in facilitated transport is obtained after norm alization for differences in capillary surface area between RG2 tumors and contralateral cortex, K-1(ACPC), partial derivative K-1(ACPC),and K-1(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 tha t facilitated transport of ACPC is upregulated across C6 and RG2 gliom a capillaries, and that tumors can induce upregulation of amino acid t ransporter expression in their supporting vasculature. They also sugge st that early imaging (e.g., 0 to 20 minutes) with radiolabeled amino acids in a clinical setting may be optimal for defining brain tumors.