Published in Cancer Detection and Prevention 2001; 25(2):183-191.

Investigating the Role of Immunomodulation for Colon Cancer Prevention: Results of an In Vivo Dose Escalation Trial of Levamisole with Immunologic Endpoints

Randall F Holcombe, MDa, Tatiana Milovanovica Ruby M. Stewartb, and Tessa M. Brodhaga

aDivision of Hematology-Oncology and the Chao Family Comprehensive Cancer Center, University of California, Irvine, and bSection of Hematology-Oncology, Louisiana State University Medical Center, Shreveport, LA

Address all correspondence and reprint requests so: Randall F. Holcombe, MD, Division of Hematology-Oncology, University of California, Irvine Medical Center, 101 The City Drive, Building 23, Orange, CA 92868.

ABSTRACT: The potential role of immunomodulatory agents for colon cancer prevention has not been studied systematically. Levamisole (LMS), which is immunostimulatory, is synergistic with 5-fluorouracil in the adjuvant therapy of patients with stage III colon cancer. This pilot study was initiated to explore the potential utility of LMS as a colon cancer prevention agent and to define the minimum dose at which it retains potentially beneficial effects on the immune system. Normal volunteers were treated over 3 days with LMS at four different dose levels and were monitored for toxicity and immunologic changes. Immunologic endpoints included lymphocyte antigen expression, serum cytokine levels, and two new ex vivo assays that defined LMS's activity in modulating T-helper-l (Thl) cytokine production. In addition, in vitro dose-response analyses of LMS's effects on cellular immune function were performed. LMS was tolerated without toxicity at low dosages only. Significant increases (P < .0001) in the proportion of peripheral blood mononuclear cells expressing the natural killer antigen CDl6 were noted at all dose levels. LMS did not alter serum cytokine levels and only minimally affected Thl cellular immune function. In vitro analysis demonstrated that LMS is synergistic with interleukin 12 in the induction of a Thl cytokine response at very low concentrations (1 µM). This study suggests that short-term LMS is only minimally immunomodulatory but that immune activity is equivalent at low dosages where the medication is better tolerated. Additional, longer-term, studies of low-dose LMS as a potential colon cancer chemopreventive agent should be considered.

KEY WORDS: cancer prevention, cellular immune response, colon cancer, immunology, levamisole.