Recombinant human tumor necrosis factor-α: Thrombus formation is a cause of anti-tumor activity

Abstract

In a previous study we showed that recombinant human tumor necrosis factor-α (rTNF-α) has no cytolytic effect on Meth A fibrosarcoma cells in vitro but that it has a strong anti-tumor activity in vivo. In the present work, we define the in vivo mode of action of rTNF-α on solid-form Meth A fibrosarcoma implanted intradermally (i.d.) in mice. rTNF-α exhibited strong anti-tumor activity when given intravenously (i.v.) 7 or 10 days after tumor implantation, but not when given 3 days after implantation. Light and electron microscopy showed that rTNF-α impaired microcirculation by producing fibrin-like substances in newly formed microcapillaries in 7-day-old tumor tissue. An anti-coagulant, dicoumarol, abrogated the effect of rTNF-α. Injection of carbon particles showed that the development of capillaries in 7-day-old tumors was more extensive than in 3-day-old tumors, and suggested that the anti-tumor activity of rTNF-α depends upon a fully developed fine network of induced capillaries in the tumor. Electron microscopy showed that rTNF-α increases the number of primary and secondary lysosomes in the cytoplasm of 7-day-old tumor cells. The results suggest that rTNF-α selectively stems the blood flow in newly formed microcapillaries, eventually leading to autolysis of the tumor cells.