Enhanced tumor uptake of carboplatin and survival in glioma-bearing rats by intracarotid infusion of bradykinin analog, RMP-7.
OBJECTIVE
Intracarotid infusion of the bradykinin analog, RMP-7, can increase permeability in brain tumor capillaries. This study sought to determine the following: 1) the unidirectional transport, Ki, of radiolabeled [14C]carboplatin into brain tumors with either intravenous or intracarotid RMP-7 infusions; 2) the duration and extent of increased permeability in tumor capillaries during continuous RMP-7 infusions; and 3) the effect on survival of carboplatin combined with RMP-7 treatment in rats with gliomas.


METHODS
Wistar rats with RG2 gliomas were used, and a unidirectional transfer constant, Ki, was determined using quantitative autoradiography. In the survival study, the rats were treated with intra-arterial carboplatin and RMP-7 at Days 5 and 7 after tumor implantation.


RESULTS
Intracarotid infusion of RMP-7 for 15 minutes increased the transport of [14C]carboplatin to tumors by 2.7-fold, as compared with saline infusion alone (P < 0.001). The transports of [14C]dextran and [14C]carboplatin into tumors were significantly higher with 15 minutes of intracarotid infusion of RMP-7 (0.1 microgram/kg/min), compared to those with 10-, 30-, or 60-minute infusions (P < 0.01). Rats treated at Days 5 and 7 after tumor implantation with carboplatin alone (10 mg/kg) exhibited a modest increase in survival at 31 days (37%, compared to < 10% of controls), while those given the combination of carboplatin with RMP-7 exhibited a significantly higher survival rate (74%).


CONCLUSIONS
Intracarotid infusion of RMP-7 can selectively increase transport of carboplatin into brain tumors and results in higher survival in rats with gliomas. These findings support the use of intracarotid infusion of RMP-7 to enhance the delivery of carboplatin to patients with malignant brain tumors.
Matsukado
K
K
Jonsson Comprehensive Cancer Center, Division of Neurosurgery, University of California, Medical Center, Los Angeles, USA.
Inamura
T
T
Nakano
S
S
Fukui
M
M
Bartus
R T
RT
Black
K L
KL
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001345:Autoradiography; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001921:Brain / Q000098:blood supply / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002339:Carotid Arteries; D004305:Dose-Response Relationship, Drug; D005260:Female; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D051381:Rats; D017208:Rats, Wistar; D015996:Survival Rate
D000970:Antineoplastic Agents; C089876:RMP 7; D016190:Carboplatin; D001920:Bradykinin