Protamine as an Anti-Angiogenesis Agent for Cancer Therapy: Blood Coagulation of Tumor Feeding Vessels Measured by MRI

Purpose Development of anti-angiogenic therapeutic agents has become increasingly important for cancer treatment since the role of angiogenesis in cancer development has been emphasized. One important aspect of the potential agents is the selectivity of action on the neovasculature, but not on the mature vessels. Mast cells are involved in the development of type I hypersensitivity reactions and are widely distributed in tissues. Many types of human and animal carcinomas, however, have been shown to accumulate large numbers of degranulating mast cells at the edges of the tumor and in the fibrovascular stroma within the tumor mass. Mast cell infiltration is significantly greater within human breast cancers than in benign breast lesions (1,2). Protamines are low-molecular weight proteins that are rich in arginine and strongly cationic. In the presence of heparin, which is strongly acidic, protamines and heparin rapidly form a stable salt in which the anticoagulant activity of heparin is neutralized (3). Because of the extensive degranulation of mast cells with deposition of heparin in adenocarcinomas, we hypothesize that protamine would be localized near the mast cells at the edges of the tumor, leading to coagulation of the tumor feeding vessels in mammary adenocarcinomas. Therefore, it may be a potential anti-angiogenic therapeutic agent for cancer treatment. To test the hypothesis, ,we compared the kinetics of Gd-DTPA before and after administration of protamine.