Cereport® (RMP-7) increases carboplatin levels in brain tumors after pretreatment with dexamethasone

Abstract

Accumulating evidence suggests that dexamethasone might decrease permeability of the blood-brain tumor barrier, further limiting the delivery of agents into brain tumors. The bradykinin B 2 receptor agonist, Cereport ® (RMP-7), selectively increases permeability of the vasculature supplying brain tumors in both animal models and humans. The present study was conducted to characterize the effects of dexamethasone on the blood-brain tumor barrier and its potential interaction with Cereport's ability to enhance penetration of radiolabeled carboplatin. Dexamethasone (1.5 mg/kg/day, twice a day) was given to RG2 glioma-bearing rats via oral gavage for 3 consecutive days. After treatment, animals received a 15-min intracarotid infusion of Cereport (4.5 µg/kg) and a bolus of [ 14 C]carboplatin. The levels of [ 14 C]carboplatin (nCi/g) in the tumor and nontumor regions were determined at 1, 14, or 24 h after the last dose of dexamethasone. Dexamethasone, alone, significantly decreased the levels of radiolabeled carboplatin permeating the tumor (19%), although there were no signi cant differences between any of the time points examined. Cereport administration signi cantly increased levels of carboplatin in the tumor, independent of whether or not dexamethasone was given (46% with and 49% without). Although the relative effects of Cereport on tumor carboplatin levels were not affected by dexamethasone, the absolute levels achieved with Cereport were modestly reduced (44 nCi/g versus 55.5 nCi/g of [ 14 C]carboplatin, with and without dexamethasone, respectively). Thus, while the data support the use of Cereport as adjunctive therapy in the treatment of glioma patients, they also warn that the use of dexamethasone may reduce delivery of chemotherapeutic agents to brain tumors, even when special pharmacologic measures are employed to enhance delivery. Neuro-Oncology 1, 268-274, 1999 (Posted to Neuro-Oncology [serial online], Doc. 99-12, September 9, 1999 D espite substantial effort to develop new antineoplastic drugs, survival of malignant glioma patients has not been signi cantly improved (Nelson et al., 1993). One reason chemotherapeutic agents have not been more successful is the existence of the BBTB 2 (Groothius et al., 1982;Long, 1970;Neuwelt et al., 1982;Shibata, 1989). While the vasculature comprising the BBTB is known to be leaky compared with normal brain (Levin et al., 1975), it still offers signi cant resistance to water-soluble chemotherapeutic agents, thus impeding the entry of these drugs into the tumor.Over the past several years, a number of different techniques have been explored to increase permeability of the BBTB, with hyperosmotic disruption of the barrier being among the earliest (Neuwelt et al., , 1985Neuwelt and Rapoport, 1984). More recently, bradykinin (Black, 1995;Matsukado et al., 1998;Nomura et al., 1994) and the bradykinin agonist Cereport ® (RMP-7) (Bartus et al., 1996a, b;Doctrow et al., 1994;Straub et al., 1994) have been used to stimulate the receptors on the endothelial cells comprising...

SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma

“…Its main organ toxicities include neurotoxicity which is less in comparison to cisplatin and oxaliplatin, ototoxicity, and nephrotoxicity with a loss of magnesium, though severe nephrotoxicity has not been reported during carboplatin therapy. Dexamethasone probably inhibits the effect of platinum compounds in glial cells [24].…”

Modulation of Intercellular Junctions by Cyclic-ADT Peptides as a Method to Reversibly Increase Blood–Brain Barrier Permeability

“…The BBB represents a significant obstacle, and there is much interest in approaches for increasing brain penetration of diagnostic and therapeutic agents. One tactic that has been used for enhancing brain penetration of drugs is transient disruption of the BBB using osmotic agents such as mannitol or pharmacological agents such as the bradykinin receptor agonist Cereport TM (RMP‐7) . In our previous studies, we have demonstrated that a linear peptide (i.e., HAV6) that binds to the external domain of cadherin can alter paracellular diffusion of various marker molecules in both in vitro and in vivo BBB models .…”

Kinin-generating cellular model obtained from human glioblastoma cell line U-373.

“…60, No 2/2013 299-305 on-line at: www.actabp.pl . Furthermore, a BK analog, Cereport, was introduced to increase the levels of chemotherapeutic agents in brain tumor and the surrounding tissue through the enhancement of permeability of the blood-brain tumor barrier (Dean et al, 1999). However, the authors emphasized the use of this B2R agonist as an adjunctive therapy.…”