Preferential Activity of Wild‐type and Mutant Tumor Necrosis Factor‐α against Tumor‐derived Endothelial‐like Cells

Abstract

Tumor-derived endothelial-like cells (tEC) were prepared by culturing human umbilical vein endothelial cells (HUVEC) in the presence of HT1080 human fibrosarcoma-conditioned medium. tEC showed higher permeability and less cell-adhesion activity than normal HUVEC (nEC). Tumor necrosis factor-α α α α (TNF) is known to have tumor-vasculature disrupting activity. tEC showed higher cytotoxicity to recombinant human TNF (rhTNF) than nEC, and was not observed using HUVEC cultured with WI38 human diploid cell-conditioned medium as a medium-control. These results demonstrate that tEC acquire physiological properties of tumor-associated vasculature, and may be a useful model system for the study of the mechanisms of TNF antitumor action. The TNF-mutant RGD-V29 (code No. F4614), which has an inserted 4 Arg-Gly-Asp sequence and an 29 Arg→ → → →Val replacement, was found to induce greater preferential destruction of tEC compared to rhTNF. When the preferential activities were evaluated in terms of 30% cytotoxicity (IC 30 ) ratio (nEC/tEC), the ratio was 460 for RGD-V29 compared to 4.2 for rhTNF. RGD-V29 also exhibited cell-adhesive function and bound preferentially to the p55 TNF-receptor. Both these properties of RGD-V29 contributed to the tEC selective cytotoxicity, indicating that the RGD ligands and selective p55 receptor binding on the cells, although uncharacterized, are involved in tEC targeting. Therefore, the TNF mutant RGD-V29 may show greater selectivity toward tumor vasculature than wild-type TNF.

RGD-avidin–biotin pretargeting to αvβ3 integrin enhances the proapoptotic activity of TNFα related apoptosis inducing ligand (TRAIL)

“…Such effects of RGD-equipped TRAIL may occur however in vivo. In addition, tumor derived growth factors might sensitize endothelial cells to TRAIL’s apoptosis inducing capacity, similar to the findings reported for TNF-sensitivity [ 32 ].…”

Enhancement of Sensitivity to Tumor Necrosis Factor α in Non–Small Cell Lung Cancer Cells with Acquired Resistance to Gefitinib

“…Recently, several new anticancer therapies using TNF-a have been developed, such as RGD-V29 (F4614) and TNF-erade (Biologic), in an attempt to reduce adverse effects (8,9,50,51). We have shown that a NSCLC cell line with acquired resistance to gefitinib acquired collateral sensitivity to TNF-a.…”

Combination of Active Components Enhances the Efficacy of Prunella in Prevention and Treatment of Lung Cancer

“…TNF-α is a cytokine that has the strongest anti-tumor activity and was found to have significant in vitro and in vivo cytotoxicity for tumor cells [ 21 ]. TNF-α can enhance the efficacy of anticancer drugs [ 22 ], inhibit selectively tumor vascular epithelial cells, display anti-angiogenic activity, cause endothelial dysfunction and igh permeability of tumor blood vessels, and induce classical and non-classical caspase-dependent apoptosis [ 23 , 24 ]. In this experiment, OD was highly correlated with the TNF-α content ( Figure 3 ).…”