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 using a model of rats injected with C6 glioma cells. Fifty four glioma-bearing rats were divided into 3 groups and treated with 0, 3, or 15 mg/kg of etoposide infused into the internal carotid artery. BBB or BTB permeability was 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 augmented significantly in proportion to the dose of etoposide. The degree of disruption of BTB was greater than that of BBB, but the rate of disruption of BBB in proportion to increasing the dose of etoposide was higher than that in the BTB. Histopathologically, no obvious changes were observed in the animals of either the control group or the 3 mg/kg group but degenerative changes 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 because of the positive reaction with TdT-mediated dUTP-biotin nick-end labeling (TUNEL) method. Our results suggest that intracarotid infusion of etoposide can increase drug delivery of concurrent antitumor agents into tumor tissue, but cerebral parenchymal cell damage is expected with a higher dosage of etoposide. Therefore, the dosage of etoposide for intracarotid infusion should be lower than 15 mg/kg in order to reduce neurotoxicity of both etoposide and concurrent anticancer drugs.
Maeda
Y
Y
Department of Neurological Surgery, Okayama University Medical School, Japan.
Matsumoto
K
K
Mizumatsu
S
S
Tamiya
T
T
Furuta
T
T
Ohmoto
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D016190:Carboplatin / Q000493:pharmacokinetics; D002339:Carotid Arteries; D005047:Etoposide / Q000008:administration & dosage* / Q000494:pharmacology; D005910:Glioma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D007269:Injections, Intra-Arterial; D008297:Male; D009368:Neoplasm Transplantation; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D016190:Carboplatin