Selective thrombosis of tumor blood vessels in mammary adenocarcinoma implants in rats

Adenocarcinomas in rats and humans frequently contain perivascular, degranu lating mast cells that release heparin. Protamine is a low-molecular weight , cationic polypeptide that binds avidly to heparin and neutralizes its ant icoagulant properties. We hypothesized that mast-cell heparin functions as a localized anticoagulant that modulates hemostasis and blood perfusion in tumors. Consequently, systemically administered protamine should be able to neutralize the endogenous heparin within tumors, thereby inducing selectiv e thrombosis of blood vessels within tumors. Here we demonstrate with magne tic resonance imaging (MRI) that an intravenous dose of protamine labeled w ith gadolinium accumulated within the parenchyma of subcutaneous implants o f a mammary adenocarcinoma in Fischer 344 rats. Moreover, we show with dyna mic contrast enhanced MRI that sequential intravenous doses of protamine in 12 tumor-bearing rats resulted in significantly decreased signal enhanceme nt kinetics (blood perfusion) of the tumor. This functional impairment of M RI signal enhancement was accompanied by histological evidence of thrombosi s In the blood vessels within the tumor. There was no histological evidence of thrombosis within normal liver, kidney, lung, spleen, or adjacent muscl e of tumor-bearing animals that received protamine treatment or in the tumo rs of animals that had not been pretreated with protamine. On the basis of these results, we conclude that protamine accumulates within adenocarcinoma implants and induces selective thrombosis of blood vessels within the tumo r, probably by neutralizing the endogenous heparin within tumors.