Etoposide-induced blood-brain barrier disruption

Effect of drug compared with that of solvents

Melvin K. SpigelmanDepartments of Neoplastic Diseases, Neurosurgery, Biomathematical Sciences, Physics-Nuclear Medicine, and Medicine, Mount Sinai School of Medicine, New York, New York

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Rosario A. ZappullaDepartments of Neoplastic Diseases, Neurosurgery, Biomathematical Sciences, Physics-Nuclear Medicine, and Medicine, Mount Sinai School of Medicine, New York, New York

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James JohnsonDepartments of Neoplastic Diseases, Neurosurgery, Biomathematical Sciences, Physics-Nuclear Medicine, and Medicine, Mount Sinai School of Medicine, New York, New York

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Stanley J. GoldsmithDepartments of Neoplastic Diseases, Neurosurgery, Biomathematical Sciences, Physics-Nuclear Medicine, and Medicine, Mount Sinai School of Medicine, New York, New York

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Leonard I. MalisDepartments of Neoplastic Diseases, Neurosurgery, Biomathematical Sciences, Physics-Nuclear Medicine, and Medicine, Mount Sinai School of Medicine, New York, New York

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James F. HollandDepartments of Neoplastic Diseases, Neurosurgery, Biomathematical Sciences, Physics-Nuclear Medicine, and Medicine, Mount Sinai School of Medicine, New York, New York

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✓ The intracarotid infusion of the anti-neoplastic compound, etoposide, has been shown to exert a dose-dependent effect on blood-brain barrier (BBB) permeability. Etoposide, however, is formulated in a complex solvent solution containing alcohol, Tween 80, polyethylene glycol 300, and citric acid. To investigate the contribution of the solvent solution to BBB disruption, the authors studied Sprague-Dawley rats after the internal carotid artery infusion of the solvent solution with and without the addition of etoposide. Experiments were performed at four doses of drug and/or solvent. Disruption of the BBB was evaluated qualitatively by the appearance of the systemically administered dye, Evans blue, in the cerebral hemispheres and quantitatively by the ratio of gamma counts of the technetium-labeled chelate of diethylenetriaminepentaacetic acid (99mTc-DTPA) in the ipsilateral:contralateral hemisphere. Significant barrier opening was obtained in all four groups of animals infused with solvent plus etoposide. In the corresponding groups of rats infused with the solvent solution alone, BBB disruption was markedly lower. Only in the group infused with the largest dose of solvent was the hemispheric ratio of 99mTc-DTPA significantly different from saline-infused animals. Each of the groups with solvent plus etoposide had 99mTc-DTPA ratios significantly different from the control group. Intracarotid infusion and subsequent BBB disruption were well tolerated by the animals receiving either solvent alone or solvent and etoposide. Disruption of the BBB secondary to the intracarotid infusion of etoposide is primarily caused by the drug itself and not by the solvent solution.

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