Bradykinin modulation of tumor vasculature: I. Activation of B-2 receptorsincreases delivery of chemotherapeutic agents into solid peripheral tumors, enhancing their efficacy

Delivery of chemotherapeutic agents to solid peripheral tumors is compromis ed because the impaired microvasculature within and surrounding tumors limi ts diffusion and convection of agents from the vasculature to the tumor. Us ing a variety of rat tumor models, we show that intravenous administration of a vasoactive bradykinin B-2 receptor agonist (Cereport, or labradimil; f ormerly RMP-7) enhances by nearly 3 times the delivery of the chemotherapeu tic agent carboplatin, as well as the larger 70-kDa marker dextran, into ec topic and orthotopic solid tumors. This effect was selective for tumor tiss ue, with little or no increase seen in nontumor tissues and organs. Additio nally, the increased carboplatin levels observed in tumors persisted for at least 90 min (the longest time point measured). In contrast to the consist ent effects with hydrophilic compounds, delivery of the lipophilic, high pr otein-binding chemotherapeutics paclitaxel and 1,3-bis[2-chloroethyl]-1-nit rourea (BNCU) was not enhanced. Administration of Cereport with either carb oplatin or another hydrophilic chemotherapeutic agent, doxorubicin, signifi cantly increased efficacy of both agents, manifested by suppression of tumo r growth and prolonged survival in tumor-bearing rats. These data demonstra te that delivery of chemotherapeutics to tumors can be pharmacologically in creased (by stimulating bradykinin B-2 receptors) without increasing the sy stemic exposure, or therefore, the toxic liability associated with higher c hemotherapeutic doses.