Keiko Ishihara1, Izumi Hayashi1,2, Shohei Yamashina3 and Masataka Majima1,2,*
1Department of Molecular Pharmacology and 3Department of Anatomy, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan
2Department of Pharmacology Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan
*Corresponding author. FAX: +81-42-778-4467, E-mail: en3m-mjm@asahi-net.or.jp
Abstract: Angiogenesis is an important event in tumor growth. We evaluated the contribution of endogenous bradykinin to tumor-associated angiogenesis and tumor growth using pharmacological approaches in mice bearing sarcoma 180 cells. The weight of implanted tumors increased in parallel with increased hemoglobin contents (a parameter to evaluate angiogenesis) over a 20-day experimental period. Daily administration of bradykinin B2-receptor antagonists, Hoe140 (0.1 and 1 mg/kg per day, local injection) or FR173657 (30 mg/kg per day, p.o.), significantly suppressed the increment in angiogenesis and tumor weight, but a B1-receptor antagonist, desArg10-Hoe140 (1 mg/kg per day), did not. Administration of a plasma kallikrein inhibitor, soybean trypsin inhibitor (3 mg/site per day), significantly suppressed angiogenesis and tumor growth. In contrast, bradykinin-degrading enzyme inhibitors, captopril and phosphoramidon (500 mg/site per day), enhanced angiogenesis and increased tumor weight. Our results suggest that bradykinin, produced by plasma kallikrein or plasma kallikrein-like enzymes, promote tumor-associated angiogenesis and tumor growth in vivo.
Keywords: Angiogenesis, Kallikrein-kinin system, Bradykinin B2 receptor, Kallikrein, Sarcoma 180
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