PT  - JOURNAL ARTICLE
AU  - Emerich, Dwaine F.
AU  - Dean, Reginald L.
AU  - Snodgrass, Pamela
AU  - Lafreniere, Denise
AU  - Agostino, Mary
AU  - Wiens, Tania
AU  - Xiong, Hua
AU  - Hasler, Brant
AU  - Marsh, Joanne
AU  - Pink, Melissa
AU  - Kim, Byong Su
AU  - Perdomo, Brigido
AU  - Bartus, Raymond T.
TI  - Bradykinin Modulation of Tumor Vasculature: II. Activation of Nitric Oxide and Phospholipase A<sub>2</sub>/Prostaglandin Signaling Pathways Synergistically Modifies Vascular Physiology and Morphology to Enhance Delivery of Chemotherapeutic Agents to Tumors
DP  - 2001 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 632--641
VI  - 296
IP  - 2
4099  - http://jpet.aspetjournals.org/content/296/2/632.short
4100  - http://jpet.aspetjournals.org/content/296/2/632.full
SO  - J Pharmacol Exp Ther2001 Feb 01; 296
AB  - 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.