Steroids decrease uptake of carboplatin in rat gliomas--uptake improved by intracarotid infusion of bradykinin analog, RMP-7.
A blood-tumor barrier (BTB) limits delivery of antitumor agents to brain tumors. This study sought to determine whether dexamethasone (DXN) treatment of rats with intracranial gliomas would 1) further impair delivery of carboplatin to brain tumors, and 2) whether intracarotid infusion of the bradykinin analog, RMP-7, would improve delivery during concurrent DXN treatment. Wistar rats with RG2 gliomas were utilized and a unidirectional transport, Ki, of radiolabeled [14C] carboplatin was determined using quantitative autoradiography. In DXN pretreatment animals, 3 mg/kg/day of DXN was administered intraperitoneally for 3 days prior to Ki determinations. At 10 days after tumor implantation, Ki of [14C] carboplatin into DXN-treated tumors and brain surrounding tumor (BST) was significantly lower compared to non-DXN treated tumors and BST (3.30 +/- 0.91 vs. 4.47 +/- 1.80, p < 0.05, and 0.94 +/- 0.84 vs. 2.18 +/- 0.79, p < 0.05, respectively). Intracarotid infusion of RMP-7 (0.1 mg/kg/min) significantly increased the Ki for carboplatin in DXN-treated tumors (6.35 +/- 3.10 vs. 3.30 +/- 0.91, p < 0.01), however, RMP-7 increased Ki to a greater extent in tumors not pretreated with DXN (12.07 +/- 3.60 vs. 4.47 +/- 1.80, p < 0.0001). Our studies show that dexamethasone decreases transport of carboplatin into brain tumors. Intracarotid infusion of RMP-7 selectively increases carboplatin transport to tumors.
Matsukado
K
K
Jonsson Comprehensive Cancer Center, UCLA Medical Center 90095-7039, USA.
Nakano
S
S
Bartus
R T
RT
Black
K L
KL
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001345:Autoradiography; D001692:Biological Transport / Q000187:drug effects; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002250:Carbon Radioisotopes; D016190:Carboplatin / Q000493:pharmacokinetics*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D007261:Infusions, Intra-Arterial; D007700:Kinetics; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; C089876:RMP 7; D003907:Dexamethasone; D016190:Carboplatin; D001920:Bradykinin