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, K-i, of radiolabeled [C-14]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, K-i, 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 [C-14]carboplatin to tumors by 2.7-fold, as compared with saline infusion alone (P < 0.001). The transports of [C-14]dextran and [C-14]carboplatin into tumors were significantly higher with 15 minutes of intracarotid infusion of RMP-7 (0.1 mu g/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%). CONCLUSION: 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.