The effect of an adenosine A2A agonist on intra-tumoral concentrations of temozolomide in patients with recurrent glioblastoma

Abstract

BackgroundThe blood–brain barrier (BBB) severely limits the entry of systemically administered drugs including chemotherapy to the brain. In rodents, regadenoson activation of adenosine A2A receptors causes transient BBB disruption and increased drug concentrations in normal brain. This study was conducted to evaluate if activation of A2A receptors would increase intra-tumoral temozolomide concentrations in patients with glioblastoma.MethodsPatients 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/m2). 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.ResultsSix 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 Tmax in brain were not significantly different.ConclusionsAlthough 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.Electronic supplementary materialThe online version of this article (10.1186/s12987-017-0088-8) contains supplementary material, which is available to authorized users.

Adenosine Receptor Agonists Exhibit Anti-Platelet Effects and the Potential to Overcome Resistance to P2Y12 Receptor Antagonists

“…When compared to adenosine, this non-selective AR agonist, exhibiting high affinity at A 1 (K i = 14 nM), A 2A (K i = 20 nM) and A 3 (K i = 25 nM) adenosine receptors and lower affinity at A 2B AR (EC 50 = 140 nM), was shown to be over 20,000 times more potent as a vasodilator and 5-10 more effective as an inhibitor of platelet aggregation in response to ADP and adrenaline [22,31]. As a result, NECA is often used as a reference compound; in the present study, it was used as a point of comparison with regadenoson and LUF5835 [29,30,32].…”

“…It demonstrates non-inferiority to adenosine for detecting reversible myocardial perfusion defects, although it is a moderately selective (K i = 290 nM), short acting A 2A AR agonist with low affinity for the remaining adenosine receptors [22,25,26]. In addition to its diagnostic application, regadenoson was considered for the treatment of inflammation and sickle cell disease, and was involved in the development of brain tumor-targeted drug delivery systems [27][28][29]. In contrast, little is known about the biological activity of LUF5835, a synthetic, atypical non-ribose compound, although it was found to display interesting selectivity for adenosine receptors.…”

Considering the Experimental Use of Temozolomide in Glioblastoma Research

“…In 1987, TMZ was evaluated in a phase I study for treatment of gliomas, got approval for recurrent GB and anaplastic astrocytoma in 1999, and, finally, was approved for first-line therapy of newly diagnosed GB in 2005 [13,26,27]. Many studies assessed basic pharmacokinetic parameters of TMZ like the absorption into the blood/plasma, its metabolism and excretion via urine in the elderly [28][29][30][31], while only a limited number of studies assessed the pharmacokinetics in infants and children [32], or the neuropharmacokinetics of TMZ including its penetration into the cerebrospinal fluid (CSF) or the peritumoural tissue [33][34][35].…”

On the Critical Issues in Temozolomide Research in Glioblastoma: Clinically Relevant Concentrations and MGMT-independent Resistance

“…The samples from five patients with recurrent glioblastoma who received oral TMZ (150 mg/m 2 BSA) were collected by intracerebral microdialysis catheters on post-operative day one and analyzed by tandem mass spectrometry. The TMZ concentration in the peritumoral tissue was 0.55 ± 0.26 µg/mL (1.49-4.17 µM) [7]. Altogether, it appears that the clinically relevant TMZ concentrations might be around 5 µM, and TMZ levels in the brain are only 20% of systemic drug levels [5][6][7].…”

“…The TMZ concentration in the peritumoral tissue was 0.55 ± 0.26 µg/mL (1.49-4.17 µM) [7]. Altogether, it appears that the clinically relevant TMZ concentrations might be around 5 µM, and TMZ levels in the brain are only 20% of systemic drug levels [5][6][7]. Therefore, all in vitro studies should evaluate TMZ effects using these low concentrations.…”