Vol. 296, Issue 2, 632-641, February 2001

Bradykinin Modulation of Tumor Vasculature: II. Activation of Nitric Oxide and Phospholipase A₂/Prostaglandin Signaling Pathways Synergistically Modifies Vascular Physiology and Morphology to Enhance Delivery of Chemotherapeutic Agents to Tumors

Dwaine F. Emerich, Reginald L. Dean, Pamela Snodgrass, Denise Lafreniere, Mary Agostino, Tania Wiens, Hua Xiong, Brant Hasler, Joanne Marsh, Melissa Pink, Byong Su Kim, Brigido Perdomo and Raymond T. Bartus

Preclinical Research and Development, Alkermes, Inc., Cambridge, Massachusetts

Intravenous infusions of the bradykinin agonist Cereport (labradimil, formerly RMP-7) enhance delivery of concomitantly administered hydrophilic chemotherapeutic agents to solid tumors. The enhanced delivery produces greater in vivo efficacy of chemotherapeutic agents, manifested as suppressed tumor growth and increased survival in tumor-bearing rats. Here we elucidate the mechanisms of action involved with this unique phenomenon, at both the physical and biochemical levels. At the physical level we demonstrate that Cereport modifies the tumor vasculature in several important ways, including transient 1) reductions in interstitial fluid pressure within the tumor, 2) increases in pore size of the vasculature, and 3) increases in total vascular surface area. All three of these changes modify tumor-specific characteristics of the vasculature known to impede drug delivery to the tumor interstitium. Biochemically, we demonstrate that the activation of both of bradykinin's major signaling pathways, the nitric oxide and phospholipase A₂/prostaglandin E₂ are necessary events. Although pharmacologically blocking either pathway greatly reduced the effects of Cereport, stimulation of either pathway alone did not enhance delivery. However, simultaneous stimulation of both pathways (without exogenous bradykinin B₂ receptor stimulation) produced a nearly 2-fold increase in delivery of carboplatin to the tumor. Thus, stimulation of endogenous bradykinin B₂ receptors induces at least two parallel biochemical cascades that act synergistically to uniquely modify the tumor vasculature in ways that increase delivery and efficacy of chemotherapeutic agents.