Neurotoxicity of chemotherapeutic agents after blood‐brain barrier modification: Neuropathological studies

Abstract

We examined in 47 dogs the effects of 5-fluorouracil, Adriamycin (doxorubicin hydrochloride), cis-platinum (cis-diamminedichloroplatinum) cyclophosphamide, and bleomycin given in association with osmotic blood-brain barrier modification. The dose of drug ranged from 100% to as little as 5 to 10% of the conventional systemic dosage. Serial neurological observation and subsequent postmortem neuropathological evaluation at times varying from 2.5 hours to 52 days after drug administration showed that cis-platinum and Adriamycin were highly neurotoxic, as evidenced by neurological deficits and pathological changes in the central nervous system parenchyma; 5-fluorouracil and bleomycin had much less, but consequential neurotoxicity; and cyclophosphamide was not associated with substantial toxicity. Intracarotid cis-platinum, unlike the other drugs, damaged the blood-brain barrier and resulted in marked neurotoxicity in the absence of osmotic blood-brain barrier opening. The neural lesions produced by these agents were not specific but were manifested as foci of hemorrhagic necrosis and edema. In addition, secondary brainstem hemorrhage was observed in animals that developed transtentorial herniation. On the basis of these studies, of five drugs studied at a wide range of doses, only cyclophosphamide appears to be safe enough to evaluate in clinical trials that utilize blood-brain barrier modification to enhance drug delivery. These studies also suggest that the lack of neurotoxicity associated with the usual administration of most chemotherapeutic agents probably stems from limited entry of drug into the brain through an intact blood-brain barrier.

Early and delayed neurotoxicity of Mitoxantrone and Doxorubicin following subarachnoid injection

“…On the basis of the previous publications [17,18,27,28] as well as the current study, it can be concluded that DXR and MXN are neurotoxic following bypass of the blood-brain-barrier. Our study indicates that a dose of 10% the LDo is almost always toxic in DXR treated animals and in MXN treated rats.…”

“…Therefore, it is not surprising that neurotoxicity has not been detected in the routine systemic use of these agents. However, neurotoxicity was observed after osmotic opening of the bloodbrain barrier in experimental animals treated with DXR [27,28]. Histopathological examination revealed necrosis and hemorrhagic infarction restricted to the areas of the barrier disruption [28].…”

“…However, neurotoxicity was observed after osmotic opening of the bloodbrain barrier in experimental animals treated with DXR [27,28]. Histopathological examination revealed necrosis and hemorrhagic infarction restricted to the areas of the barrier disruption [28]. This was found to be dose related and by lowering the doses, decreased toxicity was observed.…”

Substantial excretion of digoxin via the intestinal mucosa and prevention of long‐term digoxin accumulation in the brain by the mdrla P‐glycoprotein

“…SDZ PSC 833). For instance, in animal experiments, the administration of various cytostatic drugs after the pharmacological opening of the blood-brain barrier led to severe functional and histological neurotoxicity (Neuwelt et al, 1983). Also in patients, increased local toxicity of chemotherapeutic agents has been observed by raising drug concentrations in the brain (Kaplan & Wiernik, 1982;Siegers, 1990).…”

Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors

“…Structural abnormalities of the endothelial lining, driven by an erratic angiogenesis, include open endothelial gaps (interendothelial junctions and transendothelial channels), cytoplasmic vesicles and fenestrations that contribute to leakiness and hyperpermeability of the tumor vasculature [17]. Circumvention of the BBB, although it increases drug concentrations in the tumor, also inevitably results in high concentrations of the cytotoxic drug in the normal brain -posing a threat of severe neurotoxicity [18]. Similarly, direct intervention into delicate brain structures often results in the loss of neurological and neurocognitive functions [19][20][21].…”