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
✍ Scribed by R. L. Marquet; J. N. M. Ijzermans; R. W. F. De Bruin; W. Fiers; J. Jeekel
- Publisher
- John Wiley and Sons
- Year
- 1987
- Tongue
- French
- Weight
- 458 KB
- Volume
- 40
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
The activity and toxicity of rMuTNF, alone or combined with rat recombinant interferon gamma (rRIFNy), was tested in inbred WAG rats bearing a weakly immunogenic colon adenocarcinoma (CC53 I). The tumor was implanted S.C. or under the renal capsule. A single i.v. injection of IOpg of rMuTNF in non-tumor bearers was lethal in 3 to 5 hr, whereas 2pg was not. Doses of lpg 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 IOmg/kg indomethacin. Three intralesional injections of IOpg rMuTNF on days 0, 10 and I S into S.C. tumors (diameter I-1.5cm) led to a moderate retardation of growth in 20% of the cases. Combined with lo5 units of rRIFNy, which on i t s 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 rRlFNy 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 lOmg indomethacin alone on days 0,Z and 4 had no effect (40 f 8 mg vs. 48 f 13 mg in controls) whereas 2pg of rMuTNF on the same days resulted in significant tumor inhibition (24 f 7 mg, p<O.OOI). The combined administration of 2pg of rMuTNF and indomethacin had an effect similar to that of rMuTNF alone (25 f 9 mg). Under protection of indomethacin the rMuTNF dose was increased from 2pg to IOpg. However, this did not lead to further improvement of the results. ~