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Alteration of blood-brain-CSF barrier in experimental meningeal carcinomatosis

A morphologic and adriamycin-penetration study

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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% tumor incidence 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 µg/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 solutes. 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.

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Authors and Affiliations

  1. Department of Oncology, The Beilinson Medical Center, Petah Tiqua, Israel

    Tali Siegal, Alberto Gabizon & Raphael Catanel

  2. Department of Neurologyepartment of Neurologyepartment of Neurology, The Beilinson Medical Center, Petah Tiqua, Israel

    Tali Siegal

  3. Laboratory of Immunological Neuro-oncology, The Beilinson Medical Center, Petah Tiqua, Israel, Jerusalem, Israel

    Rachel Mizrachi

  4. Department of Pathology and the Spinal Surgery Unit, The Beilinson Medical Center, Petah Tiqua, Israel

    Uri Sandbank & Eitan Ben-David

  5. Department of Neurology, Hadassah University Hospital, Kiryat Hadassah, P.O.B. 12000, 1191120, Jerusalem, Israel

    Tzony Siegal

Authors
  1. Tali Siegal
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  2. Uri Sandbank
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  3. Alberto Gabizon
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  4. Tzony Siegal
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  5. Rachel Mizrachi
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  6. Eitan Ben-David
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  7. Raphael Catanel
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Siegal, T., Sandbank, U., Gabizon, A. et al. Alteration of blood-brain-CSF barrier in experimental meningeal carcinomatosis. J Neuro-Oncol 4, 233–242 (1987). https://doi.org/10.1007/BF00150615

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