Ultrastructural changes of the vascular endothelium after intra-arterial administration of tumor necrosis factor-alpha (TNFalpha) in rat gliomas.

The ensuing ultrastructural changes in tumor vascular endothelial cells following intra-arterial administration of tumor necrosis factor-alpha (TNFalpha) were studied in an experimental rat glioma model. C6 glioma cells were implanted in Wistar rats and then after 14 days, 5 x 10(3) U of human natural-type TNFalpha (1.7 x 10(5) U/m2) was administered through the carotid artery. The animals were sacrificed at 3 or 24 h after TNFalpha treatment. A detailed examination with transmission electron microscope revealed swelling of the tumor vascular endothelial cell nuclei and mitochondria with matrix densities at 3 h. At 24 h, these cells demonstrated the presence of high amplitude mitochondrial swelling or the violent blebbing characteristic of damaged mitochondria; the cytoplasm was swollen enormously and there were dissolution of cytoplasmic organelles and rupture of the plasma membrane. The observed findings were typical of cell necrosis and confirms yet another mechanism by which TNFalpha exerts its anti-tumor effects, that is, necrotizing effects on tumor vascular endothelium. The information appears to be important in the context of clinical application of intra-arterial TNFalpha in the treatment of malignant gliomas.