Effect of intracarotid infusion of etoposide: Modification of the permeability of the blood-brain barrier and the blood-tumor barrier in rat brain tumor model

The effect of intracarotid infusion of etoposide on the permeability of the blood-brain barrier (BBB) and brain-tumor barrier (BTB) was investigated u sing a model of rats injected with C6 glioma cells. Fifty four glioma-beari ng rats were divided into 3 groups and treated with 0, 3, or 15 mg/kg of et oposide infused into the internal carotid artery. BBB or BTB permeability w as evaluated qualitatively by the leakage of Evans blue (6 animals in each group) or quantitatively by the diffusion of carboplatin [cis-diammine (1,1 -cyclobutane-dicarboxylato) platinum(II); CBDCA] (12 animals in each group) into the normal brain or the tumor tissue. BBB and BTB disruption augmente d significantly in proportion to the dose of etoposide. The degree of disru ption of BTB was greater than that of BBB, but the rate of disruption of BB B in proportion to increasing the dose of etoposide was higher than that in the BTB. Histopathologically, no obvious changes were observed in the anim als of either the control group or the 3 mg/kg group but degenerative chang es in the neurons of the hippocampus of the infused hemisphere were seen in the 15 mg/kg group. This change is thought to be caused by apoptosis becau se of the positive reaction with TdT-mediated dUTP-biotin nick-end labeling (TUNEL) method. Our results suggest that intracarotid infusion of etoposid e can increase drug delivery of concurrent antitumor agents into tumor tiss ue, but cerebral parenchymal cell damage is expected with a higher dosage o f etoposide. Therefore, the dosage of etoposide for intracarotid infusion s hould be lower than 15 mg/kg in order to reduce neurotoxicity of both etopo side and concurrent anticancer drugs.