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Human tumor xenografts treated with recombinant human tumor necrosis factor alone or in combination with interferons
Abstract:
We have studied the activity of recombinant human tumor necrosis factor (rHuTNF) on six different human tumor xenografts derived from primary breast and bowel tumors and maintained by passage in nude mice. When 5 micrograms rHuTNF was given daily intratumorally to mice with established (approximately, 0.5 cm) tumors, total tumor regression was observed by 3-4 weeks in three of six xenograft lines. In a further two lines tumor stasis or significant slowing of growth was seen. This antitumor action was not accompanied by any consistent macroscopic change in the tumor such as necrosis, but histological examination revealed tumor cell degeneration and a large peritumoral infiltration of host inflammatory cells after 4-7 days therapy. In contrast to these data, little effect was seen when the same dose of rHuTNF was administered i.p. to nude mice bearing these tumors. In only two of six lines was any significant slowing of tumor growth seen. A 5-fold increase in the i.p. dose resulted in improved activity on only one of two xenograft lines tested. Efficacy of the i.p. rHuTNF dose could, however, be enhanced by simultaneous administration of human interferon, alpha or gamma. No obvious signs of toxicity were observed at all rHuTNF doses administered and weights of control and treated mice at the end of the experiments were comparable.
Insights
Recombinant human tumor necrosis factor (rHuTNF) showed significant antitumor activity in mouse xenografts when administered intratumorally. Intraperitoneal administration was less effective, but could be enhanced with interferons.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Recombinant human tumor necrosis factor (rHuTNF) is a cytokine with potential antitumor properties.
- Understanding the efficacy of rHuTNF against various human tumors is crucial for therapeutic development.
Purpose of the Study:
- To evaluate the antitumor activity of rHuTNF in human tumor xenografts in nude mice.
- To compare the efficacy of intratumoral versus intraperitoneal administration of rHuTNF.
- To assess the potential synergistic effects of rHuTNF with interferons.
Main Methods:
- Six human tumor xenograft lines (breast and bowel) were established in nude mice.
- Recombinant human tumor necrosis factor (rHuTNF) was administered daily intratumorally (5 µg) or intraperitoneally (5 µg or 25 µg).
- Tumor growth, regression, and histological changes were monitored; inflammatory cell infiltration was assessed.
Main Results:
- Intratumoral rHuTNF led to complete regression in 3/6 xenografts and stasis/slowing in 2/6 within 3-4 weeks.
- Histology showed tumor cell degeneration and inflammatory cell infiltration post-treatment.
- Intraperitoneal rHuTNF showed limited efficacy, with some growth slowing in 2/6 lines at 5 µg.
- Higher intraperitoneal doses (25 µg) showed marginal improvement; co-administration with interferons enhanced efficacy.
Conclusions:
- Intratumoral administration of rHuTNF is significantly more effective than intraperitoneal administration for these xenografts.
- rHuTNF induces tumor cell degeneration and inflammatory responses.
- Combination therapy with interferons may enhance the therapeutic potential of intraperitoneal rHuTNF.