The effect of an adenosine A$$subscript$$2A$atsubscriptat$ agonist on intra-tumoral concentrations of temozolomide in patients with recurrent glioblastoma

Sadhana Jackson, Jon Weingart, Edjah K. Nduom, Thura T. Harfi, Richard George, Dorothea McAreavey, Xiaobu Ye, Nicole M. Anders, Cody Peer, William D. Figg, Mark Gilbert, Michelle A. Rudek, Stuart A. Grossman

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The blood-brain barrier (BBB) severely limits the entry of systemically administered drugs including chemotherapy to the brain. In rodents, regadenoson activation of adenosine A$$subscript$$2A$atsubscriptat$ receptors causes transient BBB disruption and increased drug concentrations in normal brain. This study was conducted to evaluate if activation of A$$subscript$$2A$atsubscriptat$ receptors would increase intra-tumoral temozolomide concentrations in patients with glioblastoma. Methods: Patients scheduled for a clinically indicated surgery for recurrent glioblastoma were eligible. Microdialysis catheters (MDC) were placed intraoperatively, and the positions were documented radiographically. On post-operative day #1, patients received oral temozolomide (150 mg/m$$superscript$$2$atsuperscriptat$). On day #2, 60 min after oral temozolomide, patients received one intravenous dose of regadenoson (0.4 mg). Blood and MDC samples were collected to determine temozolomide concentrations. Results: Six patients were enrolled. Five patients had no complications from the MDC placement or regadenoson and had successful collection of blood and dialysate samples. The mean plasma AUC was 16.4 ± 1.4 h μg/ml for temozolomide alone and 16.6 ± 2.87 h μg/ml with addition of regadenoson. The mean dialysate AUC was 2.9 ± 1.2 h μg/ml with temozolomide alone and 3.0 ± 1.7 h μg/ml with regadenoson. The mean brain:plasma AUC ratio was 18.0 ± 7.8 and 19.1 ± 10.7% for temozolomide alone and with regadenoson respectively. Peak concentration and T$$subscript$$max$atsubscriptat$ in brain were not significantly different. Conclusions: Although previously shown to be efficacious in rodents to increase varied size agents to cross the BBB, our data suggest that regadenoson does not increase temozolomide concentrations in brain. Further studies exploring alternative doses and schedules are needed; as transiently disrupting the BBB to facilitate drug entry is of critical importance in neuro-oncology. and 2018 The Author(s).

Original languageEnglish (US)
Article number2
JournalFluids and barriers of the CNS
Volume15
Issue number1
DOIs
StatePublished - Jan 15 2018

Keywords

  • Adenosine A$$subscript$$2A$atsubscriptat$ agonist
  • Blood-brain barrier
  • Glioblastoma
  • High grade glioma
  • Microdialysis
  • Regadenoson
  • Temozolomide

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'The effect of an adenosine A$$subscript$$2A$atsubscriptat$ agonist on intra-tumoral concentrations of temozolomide in patients with recurrent glioblastoma'. Together they form a unique fingerprint.

Cite this