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 rad iolabeled [C-14]carboplatin into brain tumors with either intravenous or intracarotid RMP-7 infusions; 2) the duration and extent of increas ed permeability in tumor capillaries during continuous RMP-7 infusions ; and 3) the effect on survival of carboplatin combined with RMP-7 tre atment in rats with gliomas. METHODS: Wistar rats with RG2 gliomas wer e used, and a unidirectional transfer constant, K-i, was determined us ing quantitative autoradiography. In the survival study, the rats were treated with intra-arterial carboplatin and RMP-7 at Days 5 and 7 aft er 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 transpor ts of [C-14]dextran and [C-14]carboplatin into tumors were significant ly 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 carb oplatin alone (10 mg/kg) exhibited a modest increase in survival at 31 days (37%, compared to <10% of controls), while those given the combi nation of carboplatin with RMP-7 exhibited a significantly higher surv ival rate (74%). CONCLUSION: Intracarotid infusion of RMP-7 can select ively increase transport of carboplatin into brain tumors and results in higher survival in rats with gliomas. These findings support the us e of intracarotid infusion of RMP-7 to enhance the delivery of carbopl atin to patients with malignant brain tumors.