Antitumor Effect of Recombinant Human Interleukin‐1β Alone and in Combination with Natural Human Tumor Necrosis Factor‐α

Abstract

In order to investigate the antitumor effect ofrecombinant human interleukin-J.8 (IL-J.8) alone and in combination with natural human tumor necrosis factor-a (nHuTNF-a), we used female BDFI mice bearing Lewis lung carcinoma (3LL). IL-J.8 showed an antiproliferative effect against pulmonary metastatic tumors of 3LL in a dose-dependent manner. We observed 19.6±6.6, 18.6±5.3, 14.1±4.4 and 13.0±6.0 metastatic tumors at doses of 0.5, 1.0, 2.5 and 5.0/lg IL-J.8/mouse/day by daily intravenous administration (the number of metastatic tumors of the control group was 26.3 ± 8.2). Similar results were obtained by intraperitoneal administration, but in this case, mice showed a marked decrease of body weight. When IL-J.8 was administered in combination with nHuTNF-a, pulmonary metastatic tumors decreased much more than when IL-J.8 was administered alone. When the control group had 18.6 ± 12.7 metastatic tumors, the nHuTNF -a group had 12.3 ± 3.9 and the IL-J.8 group had 12.8 ± 8.0, the group which was administered both cytokines had a significantly decreased number of 5.6 ± 3.3 metastatic tumors. This antiproliferative effect of IL-J.8 in combination with nHuTNF-a was reduced by the intravenous administration of anti-asialo GM 1 antibody and carrageenan. The number of metastatic tumors was increased from 8.9±8.0 to 18.8±11.4 by anti-asialo GM 1 antibody and from 9.5 ± 6.8 to 28.0 ± 12.3 by carrageenan. It was suggested that asialo GM1-positive cells and macrophage were two of the most important effectors of the antiproliferative effect of IL-J.8 and TNF-a.

Prognostic significance of tumor necrosis factors and their receptors in nonsmall cell lung carcinoma

“…The majority of in vitro and in vivo studies of TNF have been performed with TNF-␣ and have shown an antiproliferative effect of this mediator. [27][28][29] The reason for the discrepancy between our findings and those of other studies is not clear. In comparison with TNF-␤, TNF-␣ has been found to be more unstable 39,40 and to have a more rapid dissociation rate 41 form the 75-kDa R/TNF-R2, which in some ways possibly might have affected the IHC results.…”

“…Murine experiments have shown a decrease in the number of pulmonary metastases in mice bearing Lewis lung carcinoma that are treated with TNF-␣ and interleukin-1␤. 29 However, despite promising results from in vitro and in vivo studies, clinical trials using TNF-␣ in combination with other cytokines for the treatment of patients with advanced NSCLC have yielded disappointing and conflicting results. Although Yang et al 14 In the current study, we found significant coexpression of TNF-␣, TNF-␤, TNF-R1, and TNF-R2 in NSCLC.…”

Tumour necrosis factor- α and transforming growth factor- β are significantly associated with better prognosis in non-small cell lung carcinoma: putative relation with BCL-2-mediated neovascularization

“…An antiproliferative effect of TNF-α has also been found in lung cancer cell lines where an antitumorigenic function of TNF-α has been observed (Hong et al, 1987;Munker et al, 1987;Yang et al, 1989). In vivo, Ohkura et al (1990) have reported an inhibitory effect in vivo of a combined TNF-α/IL1 treatment on pulmonary metastases in mice affected by lung carcinoma. Diffuse macrophage clustering and tumour hypoxia, frequently associated with lung cancer, may increase the level of TNF-α and/or modify the expression of TNF-α receptors, influencing the effect of this cytokine on tumour…”

The effect of various inflammatory agents on the phagocytosis and cytokine profile of mouse and rat macrophages

“…A modulatory effect of polymorphonuclear cells on macrophage TNF-a production has also been observed [38]. TNF-a and IL-1b in combination produce a more marked antitumor effect than human IL-1b alone [39]. A weaker correlation (R 2 = 0.715) was found between 3 h values of IFN-g and MIP-2, while a better correlation (R 2 = 0.8) could be observed between 3 h MIP-2 and 24 h TNF-a values.…”