Tumor Necrosis Treatment and Imaging of Solid Tumors

Abstract

A novel approach to cancer imaging and therapy utilizing necrotic cells as targets for the selective binding of monoclonal antibodies has been developed in our laboratory. Tumor Necrosis Therapy (TNT) represents a radical departure from current methods that employ monoclonal antibodies (MAbs) to bind to tumor-associated cell surface antigens and require the use of different antibodies for each type of tumor. In contrast, TNT is based upon the hypothesis that MAbs against intracellular antigens that are found in all cells and are retained by dying cells show preferential localization in malignant tumors due to the presence of abnormally permeable, degenerating cells not found in normal tissues. It has long been recognized that rapidly dividing tumors contain a proportion of degenerating or dead cells, but, with attention focused upon attempts to kill the dividing cells, the degenerating component has largely been ignored. Calculations of tumor cell loss have revealed that, in contrast to normal tissues, 30–80% of the progeny of tumor cell divisions shortly undergo degeneration. In tumors, the imperfect vasculature and impaired phagocytic response permit the accumulation of degenerating cells, often with the formation of large areas of necrosis, long recognized by pathologists to be a typical feature of malignant tumors. Thus, the accumulation within tumors of a high proportion of dying cells constitutes a major distinction between malignant tumors and normal tissues, where sporadic cell death occurs at a relatively low rate and is accompanied by a rapid and orderly removal of necrotic elements from the tissue. Since degenerating cells have permeable cell surface membranes not observed in viable cells, TNT MAbs enter and bind to their intracellular antigens in necrotic areas of the tumor. Contrarily, TNT antibodies diffusing in viable regions of the tumor and normal tissues do not bind and are removed from the circulation by normal clearance mechanisms. Hence, TNT provides a novel approach for specifically targeting necrotic regions of tumors and can be used to deliver diagnostic and therapeutic reagents into the central core of tumors.