Macroscopic and microscopic early effects of tumour necrosis factor on murine Meth A sarcoma, and relation to curative activity.

Mice with solid Meth A sarcoma in the skin received an intravenous or intralesional injection of graded doses of recombinant human tumour necrosis factor (rTNF). Local treatment caused red discolouration and necrosis of the central portion of the tumour within 24 h over a larger range of doses than intravenous treatment. Effects showed a limited dose dependence and no significant correlation with subsequent cures, which were far more frequent after local treatment. A dose of rTNF that induced about equal macroscopic necrosis by both routes caused much more pronounced microscopic effects after local administration. Effects included mitotic arrest, granulocyte margination, endothelial damage, hyperaemia, congestion, oedema, and tumour cell necrosis. rTNF did not affect the Meth A cells in vitro. Locally injected skins showed moderate vascular effects which were more marked in tumour-bearing mice, but skin necrosis was absent. Data show that quantitative histology rather than macroscopically visible necrosis correlates with cure rates. A broad interference of rTNF with tumour blood supply seems to be a major cause of the induced necrosis. Granulocytes may be involved in vascular damage. The different effects of rTNF on skin and tumour indicate that tumour vasculature has enhanced susceptibility to rTNF and probably lesser repair capacity.