We demonstrated previously that selective
thrombosis of the blood vessels of solid
tumors in mice can be achieved by targeting the extracellular domain of
tissue factor by means of an antibody to an experimentally induced marker on
tumor vascular endothelium. In the present study, we extend this finding to a naturally occurring marker of
tumor vascular endothelium,
vascular cell adhesion molecule-1 (VCAM-1).
VCAM-1 is expressed by vascular endothelial cells in
Hodgkin's disease and various solid
tumors in mice and humans. It is absent from vascular endothelial cells in normal tissues in mice, with the exception of the heart and lungs, where it is present on venules. A
monoclonal antibody to murine
VCAM-1 was covalently linked to the extracellular domain of human
tissue factor to create a "coaguligand." After i.v. administration to severe combined immunodeficient mice bearing human Hodgkin's
tumors, the coaguligand localized selectively to VCAM-1-expressing vessels, caused
thrombosis of those vessels, and retarded
tumor growth. The coaguligand also localized to VCAM-1-expressing vessels in the heart and lungs of the mice but did not induce
thrombosis in these sites. An immunohistochemical evaluation of the distribution of a monoclonal anti-
phosphatidylserine (PS) antibody in the mice showed that the VCAM-1-expressing vessels in the
tumor expressed PS, whereas the VCAM-1-expressing vessels in the heart and lungs lacked PS. The lack of thrombotic effect of the coaguligand on heart and lung vessels may be because PS is needed to provide the procoagulant surface upon which coagulation complexes can assemble. The requirement for coincident expression of the targeted marker and PS on
tumor endothelium probably contributes to the selectivity of thrombotic action and the safety of coaguligands.