APOPTOSIS OF COLORECTAL ADENOCARCINOMA (COLO-201) BY TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) AND OR INTERFERON-GAMMA (IFN-GAMMA), RESULTINGFROM DOWN-MODULATION OF BCL-2 EXPRESSION/

Fas antigen is constitutively expressed in the normal colon epithelium , but considerably diminished in most colorectal carcinomas. in the pr esent study, we examine the relationship between Fas antigen expressio n and apoptosis using the colorectal carcinoma cell line COLO 201, on which a low grade of Fas antigen is expressed. Anti-Fas antibody had n o effect on the induction of apoptosis of COLO 201. However, TNF-alpha and/or IFN-gamma, independently and additively, up-regulated Fas anti gen expression on COLO 201 and induced apoptosis in a dose-dependent m anner. Both cytokines also increased the COLO 201 sensitivity to anti- Fas antibody, resulting from the down-modulation of Bcl-2 and the up-r egulation of Bar. These findings indicate that cytokine(s) plus anti-F as antibody (which mimics natural Fas ligand) are more effective in in ducing apoptosis of COLO 201 than cytokine(s) alone. These findings su ggest that immunotherapy in combination with cytokine(s) and lymphokin e-activated killer (LAK) cells will become a more effective therapy fo r cancer than cytokine(s) or LAK cells alone, since the Fas ligand is expressed on activated T cells, natural killer cells and macrophages.