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

D. Fortin, C. I. McCormick, L. G. Remsen, R. Nixon, Edward Neuwelt, H. S. Greenberg

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20 Citations (Scopus)

Abstract

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. CONCLUSION: 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.

Original languageEnglish (US)
Pages (from-to)199-207
Number of pages9
JournalNeurosurgery
Volume47
Issue number1
DOIs
StatePublished - 2000

Fingerprint

Propofol
Blood-Brain Barrier
General Anesthesia
Anesthesia
Melphalan
Carboplatin
Methotrexate
Isoflurane
Brain Neoplasms
etoposide phosphate
Pharmaceutical Preparations
Long Evans Rats

Keywords

  • Blood-brain barrier disruption
  • Etoposide phosphate
  • Neurotoxicity
  • Propofol

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

Cite this

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title = "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",
abstract = "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. CONCLUSION: 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.",
keywords = "Blood-brain barrier disruption, Etoposide phosphate, Neurotoxicity, Propofol",
author = "D. Fortin and McCormick, {C. I.} and Remsen, {L. G.} and R. Nixon and Edward Neuwelt and Greenberg, {H. S.}",
year = "2000",
doi = "10.1097/00006123-200007000-00041",
language = "English (US)",
volume = "47",
pages = "199--207",
journal = "Neurosurgery",
issn = "0148-396X",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - 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

AU - Fortin, D.

AU - McCormick, C. I.

AU - Remsen, L. G.

AU - Nixon, R.

AU - Neuwelt, Edward

AU - Greenberg, H. S.

PY - 2000

Y1 - 2000

N2 - 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. CONCLUSION: 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.

AB - 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. CONCLUSION: 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.

KW - Blood-brain barrier disruption

KW - Etoposide phosphate

KW - Neurotoxicity

KW - Propofol

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U2 - 10.1097/00006123-200007000-00041

DO - 10.1097/00006123-200007000-00041

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SN - 0148-396X

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