Intra-arterial administration improves temozolomide delivery and efficacy in a model of intracerebral metastasis, but has unexpected brain toxicity

Leslie Muldoon, Michael A. Pagel, Joao Prola Netto, Edward Neuwelt

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

We tested the hypothesis that intra-arterial (IA) infusion of temozolomide into the internal carotid artery would safely improve drug delivery to brain and enhance chemotherapy efficacy in a chemosensitive rat brain tumor model. Quantitative autoradiography after 25 µCi 14C-temozolomide was given by oral, intravenous, or IA route of administration, or IA with osmotic blood–brain barrier disruption (BBBD) (n = 5–7 per group) showed that both IA and IA/BBBD administration increased drug delivery in tumor by over threefold compared to normal brain (P 2) increased median survival when given by oral (25.5 days), intravenous (25.5 days), or IA (33 days) route of administration, compared to 17.5 days in untreated controls (n = 8 per group; overall P 2 IA. Upon initiation of the second course of IA infusion the patient had increased heart rate, blood pressure, and rash, and the procedure was terminated without sequelae. Follow up IA infusion of temozolomide diluent in normal rats showed damaged cerebrovasculature as determined by dye leakage. These results demonstrate that IA infusion of temozolomide was toxic, with or without BBBD. We conclude that under the current formulation temozolomide is not safe for IA infusion in patients.

Original languageEnglish (US)
Pages (from-to)447-454
Number of pages8
JournalJournal of Neuro-Oncology
Volume126
Issue number3
DOIs
StatePublished - Feb 1 2016

    Fingerprint

Keywords

  • Animal model
  • Case study
  • Chemotherapy
  • Intra-arterial infusion

ASJC Scopus subject areas

  • Clinical Neurology
  • Cancer Research
  • Oncology
  • Neurology

Cite this