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.
The activity and toxicity of rMuTNF, alone or combined with rat recombinant interferon gamma (rRIFN gamma), was tested in inbred WAG rats bearing a weakly immunogenic colon adenocarcinoma (CC531). The tumor was implanted s.c. or under the renal capsule. A single i.v. injection of 10 micrograms of rMuTNF in non-tumor bearers was lethal in 3 to 5 hr, whereas 2 micrograms was not. Doses of 1 microgram 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 10 mg/kg indomethacin. Three intralesional injections of 10 micrograms rMuTNF on days 0, 10 and 15 into s.c. tumors (diameter 1-1.5 cm) led to a moderate retardation of growth in 20% of the cases. Combined with 10(5) units of rRIFN gamma, 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 rRIFN gamma regressed. The subrenal capsule assay was used to study the possible interference of indomethacin with the anti-tumor activity of rMuTNF. Tumor cubes of 6-8 mg were implanted under the renal capsule; the test was evaluated by weighing. Treatment with 10 mg indomethacin alone on days 0, 2 and 4 had no effect (40 +/- 8 mg vs. 48 +/- 13 mg in controls) whereas 2 micrograms of rMuTNF on the same days resulted in significant tumor inhibition (24 +/- 7 mg, p less than 0.001). The combined administration of 2 micrograms 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 2 micrograms to 10 micrograms. However, this did not lead to further improvement of the results.
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D007213:Indomethacin / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000627:therapeutic use*
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D007213:Indomethacin