Potential for interferon-alpha-based therapy in mesothelioma: assessment in a murine model

Our plain-English summary of Potential for interferon-alpha-based therapy in mesothelioma: assessment in a murine model, by H. Bielefeldt-Ohmann, D.R. Fitzpatrick, A.L. Marzo, et al (Journal of Interferon & Cytokine Research, 1995).

The study

• Authors: H. Bielefeldt-Ohmann, D.R. Fitzpatrick, A.L. Marzo, A.G. Jarnicki, A.W. Musk, B.W. Robinson
• Journal: Journal of Interferon & Cytokine Research
• Published: 1995;15(3):213-23
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma is an aggressive tumor, usually induced by asbestos exposure, that has a poor prognosis and is unresponsive to conventional therapy. The present study was aimed at assessing the potential for interferon-alpha (IFN-alpha)-based therapies in a murine model for malignant mesothelioma. The effect of recombinant human IFN-alpha B/D on tumor growth, alone and in combination with either of two immunomodulatory and antiproliferative agents beta-carotene or alpha-difluoromethylornithine (DFMO), was assessed. The data suggest that IFN-alpha treatment is most efficacious when commenced early in tumor development. Combination of IFN-alpha with either DFMO or dietary beta-carotene supplementation improved the effect of an otherwise suboptimal IFN-alpha therapy regimen. Both IFN-alpha and beta-carotene had in vivo stimulatory effects on immune cells, perhaps indirectly by inhibiting TGF-beta generation. The immunomodulatory effects may contribute, at least in part, to the positive antitumor and clinical activities of the treatments in this model.

In plain English

This was a laboratory experiment in mice. It did not study people or asbestos. The authors grew mouse mesothelioma cells (line AC29) under the skin or in the abdominal cavity of female CBA mice. They gave a recombinant human interferon-alpha (rhIFN-alpha B/D), alone or with DFMO in drinking water or beta-carotene in feed. Under the skin, the highest dose (1 x 10^5 units per mouse per day) significantly slowed tumor growth, though tumors kept growing. In mice with abdominal tumors given interferon alone, only those treated from the day the tumor cells were injected showed a significant response. With interferon started on day 3, adding DFMO (also from day 3) delayed illness and death significantly more than either alone. Beta-carotene, fed from 7 days before tumor cells were injected, plus interferon did significantly better than interferon alone; beta-carotene alone had no significant effect. Tumors from interferon-treated mice had more cells carrying certain immune markers, and most showed lower TGF-beta1 messenger RNA. The authors concluded that interferon-alpha, alone and with DFMO or beta-carotene, can significantly delay illness and death in this mouse model.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal experiment (syngeneic and orthotopic mouse model of malignant mesothelioma), with supporting laboratory assays
• Who was studied: Female CBA/CAH mice aged 6 to 8 weeks, from the Animal Resources Centre, Western Australia, inoculated under the skin or into the peritoneal cavity with the mouse mesothelioma cell line AC29. Group sizes were small, for example 6 placebo and 6 interferon-treated mice in one subcutaneous experiment.
• Exposure: No asbestos exposure was studied. The treatments were recombinant human interferon-alpha B/D given by daily injection into the abdomen at 1.25 x 10^4 to 1 x 10^5 units per mouse per day, alone or with DFMO (2% in drinking water) or beta-carotene (120 ppm in feed).
• Main results:
  • In mice with tumors under the skin, 1 x 10^5 units per mouse per day significantly slowed tumor growth (p less than 0.05) compared with placebo or lower doses, although the tumors continued to grow.
  • In mice with tumors in the peritoneal cavity given interferon alone, only those whose treatment began on the day of tumor challenge showed a significant response (p less than 0.001). Treatment started 3 or 6 days later did not.
  • In the laboratory dish, the interferon did not directly inhibit growth of mouse mesothelioma cells at concentrations up to 1000 units per ml.
  • In interferon-treated mice, the number of tumor-infiltrating cells labeled for CD3, CD5, CD8 and CD18 increased.
  • Only mice with tumors growing in the peritoneal cavity had significant serum levels of IL-6, and interferon treatment appeared to suppress these levels.
  • With both interferon and DFMO started on day 3 after tumor challenge, the combination was significantly better than either given alone (p less than 0.001). DFMO alone also had a significant effect compared with placebo (p less than 0.001).
  • Beta-carotene, which was started in the feed 7 days before tumor-cell injection, combined with interferon started on day 3, significantly improved clinical performance and survival compared with placebo (p less than 0.005) and with interferon alone (p less than 0.05).
  • Beta-carotene supplementation given on its own had no significant effect.
  • In normal mice without tumors, dietary beta-carotene increased spleen B and T cell numbers and increased the spleen cells' proliferation and cytokine responses to mitogen stimulation.
  • Reduced TGF-beta1 messenger RNA was seen in the majority of interferon-treated tumors. Mean densitometer values were 42.3 (standard deviation 16.7) in placebo-treated mice and 14.5 (standard deviation 20.0) in interferon-treated mice (p less than 0.05). The difference for TGF-beta2 was not statistically significant. This analysis compared placebo-treated and interferon-treated tumors only.
• The authors' conclusion: The authors concluded that interferon-alpha alone, and in combination with DFMO or beta-carotene, can significantly delay the onset of clinical signs and death in a mouse model of malignant mesothelioma. They also suggested that early treatment may be necessary when interferon-alpha is used alone, whereas the combinations can have a significant effect even when started after solid tumor growth is established.
• Limitations the authors state:
  • The authors stated that the mechanisms behind interferon-alpha's antitumor effect in the animals remain unresolved and may vary with tumor type.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Asbestos Exposure, Prognosis.

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