Journal of Neuro-Oncology4:233-242 (1987) 233 © Martinus Nijhoff Publishers, Boston - Printed in the Netherlands Alteration of blood-brain-CSF barrier in experimental meningeal carcinomatosis A morphologic and adriamycin-penetration study Tali Siegal 1,2 Uri Sandbank 4, Alberto Gabizon 1, Tzony SiegaP, Rachel Mizrachi 3, Eitan Ben-David 4 & Raphael Catane 1 Departments of ~Oncology and 2Neurology, 3the Laboratory of Immunological Neuro-oncology, Hadassah University Hospital, Jerusalem; 4Department of Pathology and 5the Spinal Surgery Unit, The Beilinson Medical Center, Petah Tiqua, Israel Keywords: blood-brain barrier, meningeal neoplasm, adriamycin, subarachnoid Abstract An experimental model of meningeal carcinomatosis has been produced by subarachnoid inoculation of B16 melanoma cells into C57BL mice. Injection of 103 viable cells was sufficient to cause 100°70 tumor inci- dence and death within a median survival time of 17 days. The tumor infiltrated diffusely the meninges of the brain and spinal cord and filled the ventricular system. Electron microscopic study of the leptomeningeal tumor revealed newly formed microvessels with fenestrated endothelium. The integrity of the blood-brain barrier was studied by the extravasation of the Evans blue and the Horseradish peroxidase tracers. Barrier disruption became evident from the seventh day on, using Evans blue. Electron microscopy study showed peroxidase activity in the luminal and abluminal sides of the meningeal microvessels, and within the tight junctions. Similar findings were noted in cortical capillaries adjacent to the meningeal tumor. Brain concentrations of Adriamycin (ADR) following administration of an intravenous dose of either 10 mg/kg or 50 mg/kg were measured on days 0 to 14 after tumor inoculation. A significant increase in mean + SEM content of whole brain ADR was observed only with the 50 mg/kg dose in days 7 to 14 (0.69+0.02 txg/g wet tissue weight) as compared to tumor-free controls (0.43_+0.01, p < 0.05). Our study suggests that barrier alteration in meningeal carcinomatosis allows extravasation of tracer so- lutes. Still, in order to achieve a significant increase in a water soluble drug penetration through the disrupted barrier, a high-dose drug regimen is required. Introduction Leptomeningeal metastases are no longer consid- ered a rare complication of systemic cancer. Recent reports indicate that it is a relatively common and clinically significant problem in patients with can- cer (1, 2). In humans, the tumor infiltrates diffusely the leptomeninges of the brain and spinal cord, the cranial and spinal nerve roots, invades cerebral or spinal cord parenchyma via the perivascular Virchow-Robin spaces and obstructs the subarach- noid spinal fluid pathways (2, 3). To date little information is available about the integrity of the blood-brain or blood cerebrospinal fluid (CSF) barrier in the presence of leptomenin- geal seeding by malignant tumors. The time course of the assumed barrier alteration caused by menin- geal tumor, and its penetration by the systemically administered drugs, carried significant importance in understanding the pathophysiology of the dis- ease and in planning therapeutic strategies. It has been suggested that neovascularization by blood vessels that lack the barrier, may play a role in alter- ation of the blood-CSF barrier (4). This was based on the therapeutic outcome of systemically ad- ministered lipid and water soluble drugs in a rat tu- Address for offprints.T Siegal, MD, Department of Neurology,Hadassah UniversityHospital, Kiryat Hadassah, P.O.B. 12000,I1 91120, Jerusalem, Israel