Unexpected neurotoxicity of etoposide phosphate administered in combination with other chemotherapeutic agents after blood-brain barrier modification to enhance delivery, using propofol for general anesthesia, in a rat model.
OBJECTIVE
Osmotic blood-brain barrier disruption (BBBD) increases brain and brain tumor delivery of chemotherapeutic agents, which results in increased efficacy against brain tumors. We previously noted that the use of propofol anesthesia for BBBD increased the percentage of successful disruptions, resulting in delivery of increased amounts of chemotherapeutic drugs. This study evaluated the neurotoxicity of combination chemotherapeutic administration with this enhanced delivery system.


METHODS
Osmotic BBBD was performed in Long-Evans rats with isoflurane (n = 11) or propofol (n = 90) anesthesia. Carboplatin and/or melphalan, methotrexate, or etoposide phosphate was administered intra-arterially (IA) after BBBD using propofol anesthesia. Animals were assessed for systemic and neurological toxicity. Animals were killed for neuropathological evaluation 30 days after treatment.


RESULTS
With propofol or isoflurane anesthesia, BBBD alone produced no systemic or neurological toxicity. Single agents were relatively non-neurotoxic when administered IA with BBBD, as were the combinations of carboplatin or melphalan with methotrexate. Etoposide phosphate in combination with any other agent was observed to be highly neurotoxic if both agents were administered after BBBD. Administration of etoposide phosphate before BBBD completely eliminated neurotoxicity, although acute pulmonary toxicity occurred with any combination of etoposide phosphate and methotrexate, regardless of the timing of administration.


CONCLUSIONS
Neurotoxicity was significantly increased for etoposide phosphate combination groups, particularly when both drugs were administered IA after BBBD. This increase in neurotoxicity may reflect on increase in drug delivery observed with propofol anesthesia. The neurotoxicity of IA administered etoposide phosphate with BBBD and propofol anesthesia could be minimized by administering etoposide phosphate IA before BBBD and administering carboplatin or melphalan IA after BBBD.
Department of Neurology, Oregon Health Sciences University, and Veterans Administration Medical Center, Portland, USA.
D
D
Fortin
C I
CI
McCormick
L G
LG
Remsen
R
R
Nixon
E A
EA
Neuwelt
D000768:Anesthesia, General; D018686:Anesthetics, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000506:poisoning*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000506:poisoning*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D004195:Disease Models, Animal; D005047:Etoposide / Q000031:analogs & derivatives* / Q000506:poisoning; D005260:Female; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D062025:Organophosphate Poisoning; D009943:Organophosphorus Compounds; D015742:Propofol; D051381:Rats; D020318:Rats, Long-Evans
D018686:Anesthetics, Intravenous; D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; C061400:etoposide phosphate; D005047:Etoposide; D015742:Propofol