The mechanism of locally enhanced production of tumor necrosis factor-alpha in tumor tissues by the administration of a new synthetic lipid A analog, ONO-4007, in hepatoma-bearing rats.

Abstract

ONO-4007 is a new synthetic lipid A analog with low endotoxic activities. We previously found that ONO-4007 induced the production of tumor necrosis factor (TNF)-alpha in rat hepatoma KDH-8 tumor tissues and brought about the regression of transplanted KDH-8 cells. By contrast, ONO-4007 did not induce TNF-alpha production in spleens and sera 90 min after treatment. In the present study we attempted to elucidate how ONO-4007 induces TNF-alpha production in tumor tissues locally. We found that extracellular matrix including gelatin, fibronectin and Matrigel did not induce TNF-alpha production in splenocytes treated with ONO-4007 in vitro. However, splenocytes co-cultured with cKDH-8/11 tumor cells in the presence of ONO-4007 produced more TNF-alpha than splenocytes cultured by themselves in the presence of ONO-4007. The stimulation of cKDH-8/11 cells in the presence of ONO-4007 for splenocytes to produce TNF-alpha depended on the type of contact between the cells. The cKDH-8/11 cells fixed in formalin were not able to induce TNF-alpha production of splenocytes even in the presence of ONO-4007. However, syngeneic fibrosarcoma cell line KMT-17/A3, allogeneic hepatocellular carcinoma cell line LDH and rat lung endotherial cell line RLE induced TNF-alpha production in splenocytes, but their stimulation was weaker than that of cKDH-8/11. The soluble form of the cKDH-8/11 cell membrane did not stimulate splenocytes to produce TNF-alpha in the presence of ONO-4007. cKDH-8/11 cells did not stimulate the splenocytes devoid of macrophages to produce TNF-alpha in the presence of ONO-4007.