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Cancer Control Research

Abstract

DESCRIPTION (Applicant's Description) Cancer prevention is an evolving field in clinical oncology. In addition to lifestyle changes (diet, smoking), there is evidence that pharmacologic intervention with cancer "chemopreventive" agents such as calcium, non-steroidal anti-inflammatory drugs and beta-carotene may be beneficial for many patients. Because of the difficulties in measuring and quantitating changes in the activity of the immune system, few immunomodulatory agents have been tested as possible candidates for cancer chemoprevention. Levamisole (LMS) is an immunostimulant which is utilized along with 5-fluorouracil (5FU) in the adjuvant therapy of patients with surgically resected stage III colon cancer. This agent is ineffective in the treatment of clinically apparent cancer but appears effective against microscopic disease, likely through stimulation of anti-tumor aspects of the immune system. Therefore, it is possible that LMS may be useful as a cancer prevention agent. Initially in this proposal, several activities of LMS which have been defined previously in patients with colon cancer will be evaluated in normal volunteers to ascertain the potential utility of LMS as a cancer chemoprevention agent. Specifically, the proportion and activity of natural killer (NK) cells will be evaluated. Increases in NK cells in colon cancer patients receiving LMS correlates with longer disease-free survival. The ability of LMS to induce a Th1-type immune response in vivo and it's activity in priming CD4-positive T-cells to be induced toward a Th1 differentiation pathway in vitro will be studied. Previous studies have suggested that LMS is synergistic with IL12 in the promotion of a Th1 response. A Th1 immune response is critical for immunity against viral and parasitic infections and against tumors. Finally, because LMS induces changes in MHC class 1 expression on colon cancer cell lines in vitro, theoretically making them more susceptible to lysis by NK cells, the effect of LMS on MHC class 1 expression on buccal mucosal cells in vivo will be determined. Information obtained in these pilot studies will then be utilized to develop a limited double-blinded placebo-controlled trial with crossover design in patients with colonic polyps. This aspect of the proposal will be of longer duration and will attempt to validate immunologic intermediate endpoints defined in the initial pilot phase. Overall, these studies will involve a clinical protocol with a dose-response design to evaluate the immunologic effects of LMS and will provide the foundation for future investigations of LMS as a cancer chemoprevention agent.