Involvement of the Kinin‐generating Cascade in Enhanced Vascular Permeability in Tumor Tissue

Abstract

Enhanced vascular permeability in tumor tissue has profound pathological consequences in tumor biology. However, details of the mechanism involved are not clear. The present work on tumor vascular permeability has led to the following three findings, (i) Ascitic tumor fluid contained kinin (about 1‐40 ng/ml), which is known to enhance vascular permeability and induce pain in vivo, (ii) Kinin is generated via the kallikrein‐dependent cascade in the ascitic tumor fluid. By blocking this kinin‐generating cascade with Kunitz‐type soybean trypsin inhibitor the formation of ascites was suppressed, (iii) Blocking of kinin‐degrading enzymes (kininases I and II) by an appropriate kininase inhibitor (e.g., captopril) may result in increased permeability, leading to accumulation of the ascitic fluid. This phenomenon was verified by an about 1.2‐1.5 fold increase in leakage of 51Cr‐labeled bovine serum albumin into the ascites when kininase inhibitors had been administered orally 30 min before intravenous administration of the bovine serum albumin.

Augmentation of tumour delivery of macromolecular drugs with reduced bone marrow delivery by elevating blood pressure

“…Recently we reported that ATI-ITinduced hypertension combined with the use of kininase inhibitor enhanced the tumour localisation of a monoclonal antibody up to 200% of control (Noguchi et al, 1992). Kininase inhibitor might enhance the vascular permeability by prolonging the action of kinin Matsumura et al, 1988;Matsumura et al, 1990;Matsumura et al, 1991).…”

A Potential Role of Bradykinin in Angiogenesis and Growth of S-180 Mouse Tumors

“…Although the involvement of BK in ascitic fluid accumulation in ascitic tumor has been reported (19,20,28), the present study is the first report demonstrating the roles of BK in tumor-related angiogenesis. As shown in Fig.…”

“…Recent studies have demonstrated that BK stimulates angiogenesis in vivo (18). Although BK is also thought to enhance vascular permeability in tumors and promote tumor growth (19,20), its involvement in enhancement of angiogenesis and consequently tumor growth has not been fully elucidated.…”

Passive targeting of nanoparticles to cancer: A comprehensive review of the literature

“…Kallikrein generates bradykinin directly from kininogen (21). Bradykinin receptors have been identified in various human and rodent solid tumors (22,23) and it was demonstrated that the bradykinin-generating cascade is activated in neoplastic tissues (24). Bradykinin is present at high levels in the peritoneal and pleural fluids of humans and animals with cancer.…”

“…The crucial role of bradykinin in the extravasation of plasma components into the peritoneal or pleural cavity was further demonstrated by the inhibition of kallikrein (19). Therefore, bradykinin, a key factor controlling vascular permeability, is an important mediator controlling the EPR effect in neoplastic tissues (11,24). Bradykinin is also known to activate NO production via the activation of endothelial NO synthase (eNOS) (25).…”