Colorectal cancer is one of the most common malignancies in both men and women in the Western world and more than 150,000 new cases will be diagnosed in 1991 in the United States alone. Despite major advances in general patient care and surgical therapy, the mortality rate associated with this disease has not changed significantly over the last 40 years. Hepatic metastasis is one of the most serious complications and 60% of patients with advanced colon adenocarcinoma will develop this disease. Objectives in this research proposal are to establish new approaches directed towards the inhibition of human colon adenocarcinoma growth with special emphasis on the study of metastatic disease to the liver. Two hepatic metastatic animal model systems have been developed in athymic nude and in severe combined immune deficient (SCID) mice respectively by injecting human colon adenocarcinoma cells into portal vein of these mice. Although these animal models do not represent all the steps of the metastatic cascade, it simulates the vascular spread and metastatic growth of tumor cells in the liver, and tumor growth is more physiological compared to subcutaneous xenograft model. In addition, it is possible to objectively test the activity of anti-tumor reagents by examining survival curves of tumor bearing mice, since all mice will die from massive tumor involvement in the liver. The following experiments are planed: 1) Study the anti-tumor effect of monoclonal antibody (Mab) directed against tumor cell surface antigen expressed in human colon cancer and examine if such Mab prolongs survival in hepatic metastatic animal model system. In this regard, in vivo anti-tumor effects produced by single and multiple administrations will be explored. The type and role of effector cells participating in anti-tumor activity will also be analyzed. A functional analysis of effector cells with respect to antibody-dependent cell mediated cytotoxicity (ADCC) and in vivo cytotoxicity will be performed. 2) Determine if Mab targets effector cells in vivo. Targeting of effector cell populations by Mab will be investigated in congenic nude mice bearing hepatic metastasis of human colon adenocarcinoma. In addition, the targeting and anti-tumor activity of human effector cells cross-linked with Mab will be tested against human colon adenocarcinoma cells grown in SCID mice and 3) Explore the strategies that may augment cytotoxicity mediated by Mab and human effector cells using the SCID mouse hepatic metastatic model. In this regard, it will be determined if targeting and cytotoxicity of human lymphokine-activated killer (LAK) cells to tumor is augmented in vivo by cross-linking with Mab directed against tumor cell surface antigen. We sincerely believe that these experiments will provide new information on the interaction of Mabs and cytokines with respect to inhibiting colon adenocarcinoma growth in the liver.
