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Neuro-Oncology 1999 1(4):268-274; doi:10.1093/neuonc/1.4.268
© 1999 by Society
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© 1999 by the Society forNeuro-Oncology

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

Reginald L. Dean, Dwaine F. Emerich, Brant P. Hasler and Raymond T. Bartus1

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 andDevelopment, 64 Sidney St., 4th Floor, Cambridge, MA 02139.


  Abstract

Accumulating evidence suggests that dexamethasone might decreasepermeability of the blood-brain tumor barrier, further limiting the deliveryof agents into brain tumors. The bradykinin B2 receptor agonist,Cereport® (RMP-7), selectively increases permeability of the vasculaturesupplying brain tumors in both animal models and humans. The present study wasconducted to characterize the effects of dexamethasone on the blood-braintumor barrier and its potential interaction with Cereport's ability to enhancepenetration of radiolabeled carboplatin. Dexamethasone (1.5 mg/kg/day, twice aday) was given to RG2 glioma-bearing rats via oral gavage for 3 consecutivedays. After treatment, animals received a 15-min intracarotid infusion ofCereport (4.5 µg/kg) and a bolus of [14C]carboplatin. The levelsof [14C]carboplatin (nCi/g) in the tumor and nontumor regions weredetermined at 1, 14, or 24 h after the last dose of dexamethasone.Dexamethasone, alone, significantly decreased the levels of radiolabeledcarboplatin permeating the tumor (19%), although there were no significantdifferences between any of the time points examined. Cereport administrationsignificantly increased levels of carboplatin in the tumor, independent ofwhether or not dexamethasone was given (46% with and 49% without). Althoughthe relative effects of Cereport on tumor carboplatin levels were not affectedby dexamethasone, the absolute levels achieved with Cereport were modestlyreduced (44 nCi/g versus 55.5 nCi/g of [14C]carboplatin, with andwithout dexamethasone, respectively). Thus, while the data support the use ofCereport as adjunctive therapy in the treatment of glioma patients, they alsowarn that the use of dexamethasone may reduce delivery of chemotherapeuticagents to brain tumors, even when special pharmacologic measures are employedto enhance delivery.

Received March 23, 1999; Accepted June 29, 1999


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