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Intracarotid Infusion of Leukotriene C4 Increases Blood-Tumor
Barrier Permeability in Experimental Rat Brain Tumors
Source: Surg Forum 1989;40:490-493.
Author: King WA, Black KL, Ikezaki K, Becker DP, Toga AW.
Abstract:
Delivery of most antitumor moieties to brain tumors is suboptimal because of the blood-brain barrier, which allows passage of only low molecular weight and hydrophobically charged substances. Even after osmotic disruption of the blood brain barrier, drug levels in tumors are only modestly increased, whereas concentrations in normal tissue are significantly increased. To circumvent this problem we have proposed a selective biochemical modulation of the blood-brain barrier specifically to open the barrier in tumors. METHODS: RG-2 gliomas were stereotactically implanted into the left hemisphere of 18 female Wistar rats. 13 days after implantation the animals were anesthetized, vessels were cannulated, and physiologic parameters were monitered. Leukotriene C4 (LTC4)or an equal volume of vehicle was infused into the carotid artery ipsilateral to the tumor for 15 minutes.After 5 minutes of infusion, 14C-labeled alpha-aminoisobutyric acid (AIB) was intravenously injected as a bolus. After LTC4 infusion the animls were killed by decapitation and the brains were rapidly removed and frozen. 20 sections of the brain were exposed to x-ray film for 14 days. After exposure the sections were stained with thionin for histologic comparison. Autoradiograms were analyzed using computer-assisted digitized densitometry and a unidirectional blood-to-brain transfer constant, Ki, was calculated by the method of Blasberg and colleagues. RESULTS: Intracarotid LTC4 infusion resulted in a twofold increase in blood-tumor barrier permeability within tumors that were 3 mm in diameter or smaller. There was no significant change in the permeability of the blood-brain barrier of the ipsilateral cortex, the contralateral cortex, or the contralateral corpus callosum. A modest increase in permeability was seen in the basal ganglia immediately adjacent to the tumors, although no tumor infiltration was seen in this area. DISCUSSION: We conclude that LTC4 can selectively open the blood-tumor barrier after intracarotid infusion without increasing permeability in the normal cortex or white matter. The permeability in some areas adjacent to the tumor is also increased after LTC4. This may represent an effect of LTC4 on abnormal tumor feeding vessels in these areas. During preliminary experiments we noted that the Ki values of large tumors ranged from 80 to 95 uL/g/min/ and was not further increasesd with LTC4 infusion. This may well approximate the maximum opening of the blood-tumor barrier. Consequently we decided to look at the effect of leukotrienes on smaller tumors, where the barrier is only partially open. Our findings support the hypothesis that LTC4 may modulate vascular permeability in tumors, based on our previous correlation between LTC4 levels and brain edema surrounding tumors in man. Finally, selective opening of the blood-tumor barrier with LTC4 for delivery of chemotherapy might avoid some of the neurotoxicity ot normal brain associated with nonselective osmotic disruption of the barrier.
Source: Surg Forum 1989;40:490-493.
Author: King WA, Black KL, Ikezaki K, Becker DP, Toga AW.
Abstract:
Delivery of most antitumor moieties to brain tumors is suboptimal because of the blood-brain barrier, which allows passage of only low molecular weight and hydrophobically charged substances. Even after osmotic disruption of the blood brain barrier, drug levels in tumors are only modestly increased, whereas concentrations in normal tissue are significantly increased. To circumvent this problem we have proposed a selective biochemical modulation of the blood-brain barrier specifically to open the barrier in tumors. METHODS: RG-2 gliomas were stereotactically implanted into the left hemisphere of 18 female Wistar rats. 13 days after implantation the animals were anesthetized, vessels were cannulated, and physiologic parameters were monitered. Leukotriene C4 (LTC4)or an equal volume of vehicle was infused into the carotid artery ipsilateral to the tumor for 15 minutes.After 5 minutes of infusion, 14C-labeled alpha-aminoisobutyric acid (AIB) was intravenously injected as a bolus. After LTC4 infusion the animls were killed by decapitation and the brains were rapidly removed and frozen. 20 sections of the brain were exposed to x-ray film for 14 days. After exposure the sections were stained with thionin for histologic comparison. Autoradiograms were analyzed using computer-assisted digitized densitometry and a unidirectional blood-to-brain transfer constant, Ki, was calculated by the method of Blasberg and colleagues. RESULTS: Intracarotid LTC4 infusion resulted in a twofold increase in blood-tumor barrier permeability within tumors that were 3 mm in diameter or smaller. There was no significant change in the permeability of the blood-brain barrier of the ipsilateral cortex, the contralateral cortex, or the contralateral corpus callosum. A modest increase in permeability was seen in the basal ganglia immediately adjacent to the tumors, although no tumor infiltration was seen in this area. DISCUSSION: We conclude that LTC4 can selectively open the blood-tumor barrier after intracarotid infusion without increasing permeability in the normal cortex or white matter. The permeability in some areas adjacent to the tumor is also increased after LTC4. This may represent an effect of LTC4 on abnormal tumor feeding vessels in these areas. During preliminary experiments we noted that the Ki values of large tumors ranged from 80 to 95 uL/g/min/ and was not further increasesd with LTC4 infusion. This may well approximate the maximum opening of the blood-tumor barrier. Consequently we decided to look at the effect of leukotrienes on smaller tumors, where the barrier is only partially open. Our findings support the hypothesis that LTC4 may modulate vascular permeability in tumors, based on our previous correlation between LTC4 levels and brain edema surrounding tumors in man. Finally, selective opening of the blood-tumor barrier with LTC4 for delivery of chemotherapy might avoid some of the neurotoxicity ot normal brain associated with nonselective osmotic disruption of the barrier.