Interleukin-2 does not cross the blood-brain barrier by a saturable transport system

1994 ◽  
Vol 34 (2) ◽  
pp. 103-109 ◽  
Author(s):  
Paul J. Waguespack ◽  
William A. Banks ◽  
Abba J. Kastin
Keyword(s):  
Blood Brain Barrier ◽  
Transport System ◽  
Interleukin 2 ◽  
Brain Barrier ◽  
Blood Brain

Transport of alpha-keto analogues of amino acids across blood-brain barrier in rats

1982 ◽  
Vol 243 (4) ◽  
pp. E272-E277
Author(s):  
A. R. Conn ◽  
R. D. Steele
Keyword(s):  
Blood Brain Barrier ◽  
Transport System ◽  
Ketone Bodies ◽  
Brain Barrier ◽  
Sodium Pentobarbital ◽  
Keto Acid ◽  
Dual Isotope ◽  
Common System ◽  
Blood Brain ◽  
Keto Acids

The transport of 14C-labeled alpha-keto acids across the blood-brain barrier (BBB) was studied in rats anesthetized with sodium pentobarbital using a modification of a single-injection dual-isotope technique. alpha-Keto acids were found to cross the BBB via a saturable carrier-mediated transport system that may be specific based on lack of inhibition by glucose, isoleucine, and ketone bodies on the uptake of tracer levels of 14C-labeled alpha-keto acids. alpha-Ketobutyrate and alpha-keto-gamma-methiolbutyrate, both straight chain keto acids, and alpha-ketoisocaproate, a branched-chain keto acid, appeared to cross the barrier by a common carrier based on cross-inhibition studies. Aromatic keto acids had no effect on the uptake of tracer levels of these 14C-keto acids. The Km of transport of alpha-ketobutyrate, alpha-ketoisocaproate, and alpha-keto-gamma-methiolbutyrate, was 0.11, 0.60, and 0.33 mM, respectively. The corresponding Vmax was 15.7, 73.3, and 30.2 nmol . g-1 . min-1. Phenylpyruvate was found not to cross the BBB. Inhibition of brain uptake of alpha-keto acids by propionate and pyruvate, and not by DL-beta-hydroxybutyrate suggests that alpha-keto acids and monocarboxylic acids are transported either via a common system independent of ketone bodies or share an affinity with a monocarboxylic acid and an alpha-keto acid transport system.

Penetration of recombinant interleukin-2 across the blood-cerebrospinal fluid barrier

1988 ◽  
Vol 69 (1) ◽  
pp. 29-34 ◽  
Author(s):  
Stephen C. Saris ◽  
Steven A. Rosenberg ◽  
Robert B. Friedman ◽  
Joshua T. Rubin ◽  
David Barba ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Interleukin 2 ◽  
Albumin Level ◽  
Brain Barrier ◽  
Lymphokine Activated Killer Cells ◽  
Content Type ◽  
Blood Brain ◽  
Recombinant Interleukin 2 ◽  
Fine Print

✓ Recombinant interleukin-2 (rIL-2) is an immunotherapeutic agent with efficacy against certain advanced cancers. The penetration of rIL-2 across the blood-cerebrospinal fluid (CSF) barrier was studied in 12 cancer patients who had no evidence of tumor involvement of the central nervous system. At different times during treatment with intravenous rIL-2, CSF was withdrawn either continuously for 8 to 26 hours via a lumbar subarachnoid catheter (in eight patients) or by a single lumbar puncture (in four). Bioassay showed the appearance of rIL-2 in lumbar CSF 4 to 6 hours after the first intravenous dose, a rise over 2 to 4 hours to a plateau of 3 to 9 U/ml, and clearance to less than 0.1 U/ml by 10 hours after the last dose. An abnormally elevated CSF albumin level in two of the twelve patients indicated alteration of the blood-brain barrier. There were no abnormalities in the CSF glucose level or white blood cell count. The CSF pharmacokinetics contrast with the rapid elimination of rIL-2 from plasma and demonstrate significant blood-CSF barrier penetration. These data support the possibility of achieving CSF levels of rIL-2 that are adequate to maintain activity of lymphokine-activated killer cells after parenteral administration, and argue for rIL-2-associated disruption of the human blood-brain barrier in some patients.

The effect of interleukin-2 on the blood-brain barrier in the 9L gliosarcoma rat model

1989 ◽  
Vol 70 (1) ◽  
pp. 92-96 ◽  
Author(s):  
Joseph T. Alexander ◽  
Stephen C. Saris ◽  
Edward H. Oldfield
Keyword(s):  
Blood Brain Barrier ◽  
Interleukin 2 ◽  
Brain Barrier ◽  
High Dose ◽  
Normal Brain ◽  
Content Type ◽  
Tumor Bearing ◽  
Blood Brain ◽  
Significant Difference ◽  
Fine Print

✓ Carbon-14-labeled aminoisobutyric acid was used to determine local blood-to-tissue transfer constants in 22 Fischer rats with intracerebral 9L gliosarcomas that received either high-dose parenteral interleukin-2 (IL-2) or a control injection. In tumor and peritumoral tissue, the transfer constants in the IL-2-treated animals (89.6 ± 14.6 and 35.8 ± 6.0, respectively, mean ± standard error of the mean) were larger (p < 0.05) than in control animals (61.4 ± 6.4 and 14.6 ± 2.2, respectively). In contrast, in normal frontal and occipital tissue contralateral to the tumor-bearing hemisphere, there was no significant difference between the transfer constants in IL-2-treated and control animals. Furthermore, treatment of animals with IL-2 excipient caused no change in permeability as compared to animals treated with Hanks' balanced salt solution. Parenteral injection of IL-2 increases blood-brain barrier disruption in tumor-bearing rat brain but does not increase the vascular permeability of normal brain. Methods to prevent this increased tumor vessel permeability are required before parenteral IL-2 can be used safely for the treatment of primary or metastatic brain tumors.

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