Assessment of protamine-induced thrombosis of tumor vessels for cancer therapy using dynamic contrast-enhanced MRI

Abstract

Since the role of angiogenesis in cancer development has been recognized, the study of anti-angiogenic or anti-vascular therapeutic agents has become increasingly important for cancer treatment. Selective thrombosis is one approach towards this goal. Since many types of carcinoma accumulate large numbers of degranulating mast cells which will release heparin, intravenously injected protamine may bind to heparin, neutralize its anti-coagulant effect and induce thrombosis. In this work we studied the formation of thrombosis by using dynamic contrast enhanced MRI. The enhancement kinetics of the contrast medium measured before and after protamine treatment were compared to assess the thrombotic effect. The underlying concept was that if the vessels became clotted, the subsequently injected contrast medium could not be delivered into the tissue to cause enhancement. In addition to the tissue-specific changes, protamine may also induce systemic effect in the host. The therapy-induced changes measured in tumors were compared to changes in normal tissues: liver, kidney, and especially the muscle adjacent to tumor. The results showed that protamine induced pronounced changes in the tumor. However, the degree of change measured by MRI was not associated with the results of semiquantitative assessment of thrombosis assessed by histology, perhaps due to the heterogeneous nature of the tumor and the difficulty in sampling sufficient regions histologically. The protamine-induced temporal effects were also studied. We demonstrated that protamine could induce selective thrombosis in tumors, and that the effect could last for several hours. Dynamic contrast-enhanced MRI can serve as a suitable means to investigate the mechanism of this novel approach to induce selective thrombosis for anti-vascular cancer therapy. Copyright © 2002 John Wiley & Sons, Ltd.