RT Journal Article SR Electronic T1 Bradykinin Modulation of Tumor Vasculature: I. Activation of B2 Receptors Increases Delivery of Chemotherapeutic Agents into Solid Peripheral Tumors, Enhancing Their Efficacy JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 623 OP 631 VO 296 IS 2 A1 Dwaine F. Emerich A1 Pamela Snodgrass A1 Reginald L. Dean A1 Denise Lafreniere A1 Mary Agostino A1 Tania Wiens A1 Hua Xiong A1 Brant Hasler A1 Joanne Marsh A1 Melissa Pink A1 Byong Su Kim A1 Raymond T. Bartus YR 2001 UL http://jpet.aspetjournals.org/content/296/2/623.abstract AB Delivery of chemotherapeutic agents to solid peripheral tumors is compromised because the impaired microvasculature within and surrounding tumors limits diffusion and convection of agents from the vasculature to the tumor. Using a variety of rat tumor models, we show that intravenous administration of a vasoactive bradykinin B2 receptor agonist (Cereport, or labradimil; formerly RMP-7) enhances by nearly 3 times the delivery of the chemotherapeutic agent carboplatin, as well as the larger 70-kDa marker dextran, into ectopic and orthotopic solid tumors. This effect was selective for tumor tissue, with little or no increase seen in nontumor tissues and organs. Additionally, the increased carboplatin levels observed in tumors persisted for at least 90 min (the longest time point measured). In contrast to the consistent effects with hydrophilic compounds, delivery of the lipophilic, high protein-binding chemotherapeutics paclitaxel and 1,3-bis[2-chloroethyl]-1-nitrourea (BNCU) was not enhanced. Administration of Cereport with either carboplatin or another hydrophilic chemotherapeutic agent, doxorubicin, significantly increased efficacy of both agents, manifested by suppression of tumor growth and prolonged survival in tumor-bearing rats. These data demonstrate that delivery of chemotherapeutics to tumors can be pharmacologically increased (by stimulating bradykinin B2 receptors) without increasing the systemic exposure, or therefore, the toxic liability associated with higher chemotherapeutic doses.