In a previous study we showed that recombinant human tumor necrosis factor-a (rTNF-tr) has no cytolytic effect on Meth A fibrosarcoma cells in virro 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-a on solid-form Meth A fibrosarcoma implanted intradermally (i.d.) in mice. rTNF-a 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-ru impaired microcirculation by producing fibrin-like substances in newly formed microcapillaries in 7day-old tumor tissue. An anti-coagulant, dicoumarol, abrogated the effect of rTNF-u. 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 sug gested that the anti-tumor activity of rTNF-a depends upon a fully developed fine network of induced capillaries in the tumor. Electron microscopy showed that rTNF-a increases the number of primary and secondary lysosomes in the cytoplasm of 7-day-old tumor cells. The results suggest that rTNF-Lu selectively stems the blood flow in newly formed microcapillaries, eventually leading to autolysis of the tumor cells.
'To whom reprint requests should be sent.