Investigating the role of immunomodulation for colon cancer prevention: Results of an in vivo dose escalation trial of levamisole with immunologic endpoints

The potential role of immunomodulatory agents for colon cancer prevention h as not been studied systematically. Levamisole (LMS). which is immunostimul atory, is synergistic with 5-fluorouracil in the adjuvant therapy of patien ts with stage III colon cancer. This pilot study was initiated to explore t he potential utility of LMS as a colon cancer prevention agent and to defin e the minimum dose at which it retains potentially beneficial effects on th e immune system. Normal volunteers were treated over 3 days with LMS at fou r different dose levels and were monitored for toxicity and immunologic cha nges. Immunologic endpoints included lymphocyte antigen expression. serum c ytokine levels, and two new ex vivo assays that defined LMS's activity in m odulating T-helper-l (Th1) cytokine production. In addition, in vitro dose- response analyses of LMS's effects on cellular immune function were perform ed. LMS was tolerated without toxicity at low dosages only. Significant inc reases (P < .0001) in the proportion of peripheral blood mononuclear cells expressing the natural killer antigen CD16 were noted at all dose levels. L MS did not alter serum cytokine levels and only minimally affected Th1 cell ular immune function. In vitro analysis demonstrated that LMS is synergisti c with interleukin 12 in the induction of a Th1 cytokine response at very l ow concentrations (1 muM) This study suggests that short-term LMS is only m inimally immunomodulatory but that immune activity is equivalent at low dos ages where the medication is better tolerated. Additional, longer-term, stu dies of low-dose LMS as a potential colon cancer chemopreventive agent shou ld be considered.