Local and systemic toxicities associated with hepatic arterial infusion of human recombinant tumor necrosis factor (rTNF) were studied in healthy adult mongrel dogs. The animals received saline containing human serum albumin with or without rTNF (0.02, 0.2, or 2.0 mg/m2). Arteriograms were made, and blood samples were collected for hematologic and biochemical analyses at regular intervals. The dogs were killed at 1,3, and 7 days postinfusion and complete necropsies were performed. Specimens were obtained from various tissues for histopathologic evaluation. Results indicated that all but the highest dose of rTNF were well tolerated. Severe histopathologic changes were found in the liver, spleen, and kidneys of the animals receiving 2.0 mg/m2 rTNF. In addition, focal tubular degeneration was found in one dog administered 0.2 mg/m2 rTNF. These data suggest that the upper dose limit for hepatic arterial infusion of rTNF is between 0.2 and 2.0 mg/m2 and that renal function should be closely monitored after infusion.
Cancer 63:2096-2102, 1989.
N ANIMALS with subcutaneously induced tumors, ad-I ministration of bacterial endotoxin has been shown to produce a reduction in tumor size as a result of hemorrhagic necrosis.' The same response has been noted in patients receiving a mixed vaccine and in those with acute bacterial infection.2
In 1975, Carswell et al. found that serum from mice sensitized to bacillus Calmette-Guerin (BCG) for 2 weeks and then challenged with endotoxin contained a substance that caused hemorrhagic necrosis of subcutaneously transplanted murine tum01-s.~ This mediating substance was named tumor necrosis factor (TNF) and was believed to be produced by activated macrophages in response to endotoxin challenge. Matthews and Watrius reported that