Recombinant human tumor necrosis factor-alpha: thrombus formation is a cause of anti-tumor activity.
In a previous study we showed that recombinant human tumor necrosis factor-alpha (rTNF-alpha) 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-alpha on solid-form Meth A fibrosarcoma implanted intradermally (i.d.) in mice. rTNF-alpha 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-alpha 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-alpha. 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-alpha depends upon a fully developed fine network of induced capillaries in the tumor. Electron microscopy showed that rTNF-alpha increases the number of primary and secondary lysosomes in the cytoplasm of 7-day-old tumor cells. The results suggest that rTNF-alpha selectively stems the blood flow in newly formed microcapillaries, eventually leading to autolysis of the tumor cells.
Shimomura
K
K
Department of Pharmacology, Product Development Laboratories, Fujisawa Pharmaceuticals, Osaka, Japan.
Manda
T
T
Mukumoto
S
S
Kobayashi
K
K
Nakano
K
K
Mori
J
J
D000230:Adenocarcinoma / Q000473:pathology* / Q000648:ultrastructure; D000818:Animals; D003110:Colonic Neoplasms / Q000473:pathology* / Q000648:ultrastructure; D005260:Female; D005354:Fibrosarcoma / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D009336:Necrosis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
D014409:Tumor Necrosis Factor-alpha