Studies will be undertaken to characterize human tumor necrosis factor and its biological and biochemical effects. An assay will also be developed which will allow for a determination of the responsiveness of freshly removed tumor tissues to tumor necrosis factor. Studies proposed include the further characterization of the human tumor necrosis factor produced by the LuKII cell line (termed tumor necrosis factor (LuKII)) and a comparison o its biological and biochemical characteristics with those of other cytotoxic molecules which are being produced by recombinant technology (i.e., lymphotoxin and tumor necrosis factor). Studies will be undertaken to determine the relationship between and the characteristics of the various molecular weight forms of tumor necrosis factor (LuKII). Cells which have been made resistant to the growth inhibitory effect of tumor necrosis factor (LuKII) by selecting from a tumor necrosis factor-sensitive cell line those cells that are capable of growing in the presence of this factor have been found to release a protein into the media that blocks the binding of tumor necrosis factor (LuKII) to tumor necrosis factor-sensitive cells. The mechanism by which this molecule manifests its effect will be studied and the role this molecule plays in the natural resistance of cells to tumor necrosis factor (LuKII) will be investigated. Cells sensitive to the effects of tumor necrosis factor (LuKII) have been observed to have receptors for tumor necrosis factor (LuKII) and to synthesize new proteins in response to treatment with this factor. Based on these observations, methodologies will be developed which will allow for a determination of the responsiveness of freshly removed tumor tissues to the tumor necrosis factors. These determinations will be accomplished by assessing either the presence of receptors to tumor necrosis factor or the ability of the tumors to synthesize the proteins induced by tumor necrosis factor. The assessment of the responsiveness of the fresh tumor tissues to tumor necrosis factor, as proposed, would not require the growth of the tumor cells in vitro and could be done rapidly, thereby allowing clinicians to select for tumor necrosis factor therapy those patients who are capable of responding to this factor.
