QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dean, R. L. Articles by Bartus, R. T. Search for Related Content PubMed PubMed Citation

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

Alkermes, Inc., Cambridge, MA 02139

¹ Address correspondence and reprint requests to Raymond T. Bartus, Ph.D., Alkermes, Inc., Senior Vice President of Pre-Clinical Research and Development, 64 Sidney St., 4th Floor, Cambridge, MA 02139.

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 B₂ 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 [¹⁴C]carboplatin. The levels of [¹⁴C]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 significant differences between any of the time points examined. Cereport administration significantly 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 [¹⁴C]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.