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Recombinant human tumor necrosis factor-alpha: evidence of an indirect mode of antitumor activity
Abstract:
The antitumor activity of recombinant human tumor necrosis factor (rTNF-alpha) was examined on murine tumors in mice and in cultured cells in vitro. Mice were implanted intradermally with Meth A fibrosarcoma (Meth A) on day 0. rTNF-alpha caused tumor necrosis and inhibited the tumor growth when given i.v. on day 7 or 10, but not when given on day 3. When rTNF-alpha was given i.v. in doses of 0.1-3.2 micrograms/mouse twice a week for 3 weeks beginning on day 7 or 11, the growth of solid Meth A, Colon 26 adenocarcinoma, Colon 38 carcinoma, Sarcoma-180, and M5076 reticulum cell sarcoma tumors implanted s.c. or intradermally was markedly inhibited, and the life of the mice bearing these tumors, except M5076 reticulum cell sarcoma, was prolonged. The growth of Meth A implanted i.m. was also markedly inhibited by rTNF-alpha given i.v. However, the life of mice bearing i.p. Colon 26 adenocarcinoma, MH134 hepatoma, Sarcoma-180, and Ehrlich carcinoma was not prolonged by rTNF-alpha given i.p. nine times (days 1-9) in doses up to 1.0 or 3.2 micrograms/mouse. Only in the case of mice bearing i.p. Meth A, the life was slightly prolonged by i.p. treatment with rTNF-alpha but not by i.v. treatment. In experiments against in vitro cultured cells, rTNF-alpha did not show any direct cytotoxicity against mouse tumor cells: Meth A, Colon 26 adenocarcinoma, Colon 38 carcinoma, and Sarcoma-180, but had a cytotoxic effect against L929 mouse fibroblast. The results suggest that rTNF-alpha is a unique antitumor drug with potent necrotizing activity against solid tumors in mice, and that this activity may derive from indirect mechanisms related to the growth of tumors and not to the direct cytotoxicity of the drug.
Insights
Recombinant human tumor necrosis factor-alpha (rTNF-alpha) effectively inhibits solid murine tumor growth and prolongs survival. Its antitumor activity appears to stem from indirect mechanisms rather than direct cytotoxicity to tumor cells.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Recombinant human tumor necrosis factor-alpha (rTNF-alpha) is a cytokine with potential therapeutic applications.
- Understanding its antitumor mechanisms is crucial for developing effective cancer treatments.
Purpose of the Study:
- To evaluate the antitumor activity of rTNF-alpha against various murine tumors in vivo.
- To investigate the direct cytotoxic effects of rTNF-alpha on cultured tumor cells in vitro.
Main Methods:
- Murine tumor models (Meth A fibrosarcoma, Colon 26 adenocarcinoma, etc.) were established in mice.
- rTNF-alpha was administered intravenously or intraperitoneally at different time points and doses.
- Tumor growth inhibition, survival rates, and direct cytotoxicity on cultured tumor cells were assessed.
Main Results:
- rTNF-alpha demonstrated significant inhibition of solid tumor growth and prolonged survival in mice bearing various tumors when administered at specific stages of tumor development.
- Intravenous administration of rTNF-alpha was effective against solid tumors, while intraperitoneal administration showed limited efficacy.
- rTNF-alpha exhibited direct cytotoxicity against L929 mouse fibroblasts but not against the tested murine tumor cell lines in vitro.
Conclusions:
- rTNF-alpha possesses potent antitumor activity against solid murine tumors, primarily through indirect mechanisms.
- The timing and route of administration are critical factors for the efficacy of rTNF-alpha therapy.
- Further research into the indirect mechanisms of rTNF-alpha is warranted for its clinical application.