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Human lymphotoxin has at least equal antitumor activity in comparison to human tumor necrosis factor but is less
Z Qin1, L J van Tits, W A Buurman
1Max-Delbrück-Center of Molecular Medicine, Berlin, Germany.
Abstract:
Because of the severe toxicity of systemically applied tumor necrosis factor (TNF) in cancer patients, considerable efforts have been made to construct mutant TNF molecules, which retain antitumor activity, but display less toxicity. We compared tumor suppression in relation to the toxic effects of human TNF and human lymphotoxin (LT) in mice. The genes for these two cytokines were expressed in Chinese hamster ovary (CHO) cells. Intraperitoneal injection of parental and gene modified CHO cell lines producing similar amounts of biologically active TNF or LT, respectively, into nude mice showed that CHO-TNF cells killed the mice more rapidly than parental cells, but that CHO-LT tumor bearing mice lived significantly longer than mice injected with parental cells. Injection of the cells subcutaneously into severe combined immunodeficiency (SCID) mice allowed direct comparison of tumor suppression and toxic effects of the two cytokines. Both TNF and LT produced by the tumor effectively suppressed tumor growth by an indirect mechanism, LT being at least as effective as TNF. However, mice bearing CHO-TNF cells either died rapidly or developed cachexia, as shown by weight loss. In contrast, mice injected with CHO-LT cells never rapidly died and became cachectic much later than CHO-TNF cell injected animals, though serum levels of LT were higher than those of TNF. Analysis of soluble forms of TNF receptors (TNF-R1 and TNF-R2) in sera of tumor bearing mice showed that soluble TNF-R1 was downregulated in both CHO-TNF and CHO-LT, in comparison with CHO-neo cell injected mice and to normal SCID mice. The soluble form of TNF-R2 was induced by CHO cell lines. In CHO-TNF cell injected SCID mice, serum levels were significantly increased, whereas in mice injected with CHO-LT cells, serum levels of soluble TNF-R2 were decreased. Together, our results show a higher therapeutic index of LT compared with TNF.
Insights
Human lymphotoxin (LT) demonstrates a higher therapeutic index than tumor necrosis factor (TNF) for cancer treatment. LT effectively suppresses tumors with reduced toxicity and cachexia compared to TNF in preclinical models.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Systemic administration of tumor necrosis factor (TNF) causes severe toxicity in cancer patients.
- Development of less toxic TNF variants with retained antitumor activity is a significant research goal.
- Comparison of TNF and lymphotoxin (LT) in preclinical models is crucial for therapeutic development.
Purpose of the Study:
- To compare the tumor suppression efficacy and toxic effects of human TNF and human LT in mouse models.
- To evaluate the therapeutic index of LT relative to TNF for potential cancer therapies.
Main Methods:
- Genes for human TNF and LT were expressed in Chinese hamster ovary (CHO) cells.
- CHO cell lines producing TNF or LT were injected into nude and severe combined immunodeficiency (SCID) mice.
- Tumor growth, animal survival, cachexia, and serum levels of cytokines and soluble TNF receptors (TNF-R1, TNF-R2) were analyzed.
Main Results:
- Both TNF and LT suppressed tumor growth indirectly, with LT being as effective as TNF.
- Mice injected with CHO-TNF cells exhibited rapid mortality and cachexia, unlike those injected with CHO-LT cells.
- Soluble TNF-R1 was downregulated by both TNF and LT, while soluble TNF-R2 levels differed significantly between TNF and LT treatments.
Conclusions:
- Human lymphotoxin (LT) exhibits a higher therapeutic index than tumor necrosis factor (TNF) due to reduced toxicity and cachexia.
- LT represents a promising alternative to TNF for developing safer and effective cancer therapies.
- Differential modulation of soluble TNF receptors suggests distinct mechanisms of action for TNF and LT.