Anti‐tumor activity of recombinant mouse tumor necrosis factor (TNF) on colon cancer in rats is promoted by recombinant rat interferon gamma; toxicity is reduced by indomethacin

Publisher Website
Google Scholar
Abstract
The activity and toxlcity of rMuTNF, alone or combined with rat recombinant interferon gamma (rRIFNγ), was tested in inbred WAG rats bearing a weakly immunogenic colon adeno carcinoma (CC531). The tumor was implanted s.c. or under the renal capsule. A single i.v. injection of 10μg of rMuTNF in non‐tumor bearers was lethal in 3 to 5 hr, whereas 2μg was nat. Doses of 1μg rMuTNF were well tolerated when given daily for one week. The most prominent toxic feature was hemorrhagic colitis which could be alleviated when rMuTNF was preceded by i.p. administration of 10mg/kg indomethacin. Three intralesional injections of 10μg rMuTNF on days 0, 10 and 15 into s.c. tumors (diameter 1–1.5cm) led to a moderate retardation of growth in 20% of the cases. Combined with 105 units of rRIFNμ, which on its own had no effect, the overall response rate (arrest of tumor growth or regression) was 50%. Two out of 20 tumors treated intralesionally with rMuTNF and rRlFNγ regressed. The subrenal capsule assay was used to study the possible interference of indomethacin with the anti‐tumor activity of rMuTNF. Tumor cubes of 6–8mg were implanted under the renal capsule; the test was evaluated by weighing. Treatment with 10mg indomethacin alone on days 0, 2 and 4 had no effect (40 ± 8 mg vs. 48 ± 13 mg in controls) whereas 2μg of rMuTNF on the same days resulted in significant tumor inhibition (24 ± 7 mg, p < 0.001). The combined administration of 2μg of rMuTNF and indomethacin had an effect similar to that of rMuTNF alone (25 ± 9 mg). Under protection of indomethacin the rMuTNF dose was increased from 2μg to 10μg. However, this did not lead to further improvement of the results.