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Immunological effects of levamisole in vitro
J H Schiller1, M Lindstrom, P L Witt
1Department of Human Oncology, William S. Middleton Veterans Administration Hospital, Madison, WI 53705.
Insights
Levamisole, an anthelminthic drug, did not significantly alter key immune cell functions in vitro. This study suggests levamisole
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Levamisole, an anthelminthic, exhibits immunomodulatory properties.
- Previous reports suggest levamisole enhances antitumor activity with 5-fluorouracil in colorectal cancer.
- The precise mechanism of levamisole's purported antitumor effect remains unclear.
Purpose of the Study:
- To investigate the in vitro immunomodulatory effects of levamisole.
- To assess levamisole's impact on monocyte and lymphocyte functions.
- To evaluate levamisole's influence on cytokine production and antigen expression.
Main Methods:
- Peripheral blood mononuclear cells from healthy donors were incubated with varying levamisole concentrations (0.1–100 µg/ml).
- Assessed were cytotoxicity, activation, proliferation, cytokine-induced protein induction, and tumor-associated antigen expression.
- Specific immune parameters included synthetase activity, tumor necrosis factor, Fc receptor, NK/LAK cytotoxicity, T-lymphocyte activation markers (CD3-CD56), and tumor antigens (880364, NRCO-4, ING-1, ICAM-1).
Main Results:
- Levamisole showed no consistent effect on 2',5'-oligoadenylate synthetase or indoleamine-2,3-dioxygenase activity, or tumor necrosis factor production.
- No significant impact was observed on monocyte cytotoxicity, HLA-DR/DQ/DP expression, or Fc receptor expression.
- Levamisole did not significantly affect NK/LAK cytotoxicity, T-lymphocyte activation markers, lymphocyte proliferation, or the expression of tested tumor-associated antigens and ICAM-1.
Conclusions:
- Levamisole does not appear to be a potent modulator of the examined in vitro immune parameters.
- The study did not identify immunomodulatory mechanisms to explain levamisole's clinical efficacy in colorectal cancer.
- Further research is needed to elucidate the mechanism behind the observed clinical synergy between levamisole and 5-fluorouracil.
Abstract:
Levamisole, an anthelminthic drug with immunological properties, has recently been reported to have antitumor activity when administered with 5-fluorouracil in patients with Duke's C colorectal carcinoma. The mechanism of this antitumor effect is unknown, but has been postulated to be related to levamisole's immunomodulatory properties. To define further the immunomodulatory activities of levamisole, we studied the in vitro effects of levamisole on monocyte and lymphocyte cytotoxicity, activation, and proliferation; induction of cytokine-induced proteins; and expression of tumor-associated antigens. Experiments utilized peripheral blood mononuclear cells from normal donors incubated in the presence of increasing concentrations of levamisole (0.1 to 100 micrograms/ml). Levamisole had no consistent effect on induction of 2',5'-oligoadenylate synthetase activity or indoleamine-2,3-dioxygenase activity, or production of tumor necrosis factor. Levamisole had no effect on monocyte cytotoxicity or expression of HLA-DR, HLA-DQ, HLA-DP, and the Fc receptor. Similarly, levamisole had no significant effect on NK or LAK cytotoxicity or the immunological activation of T-lymphocytes, assessed by expression of CD3, CD4, CD8, CD16, CD25, and CD56. Proliferation of lymphocytes from normal donors, patients with benign polyps, and patients with malignancies, with or without IL-2 or irradiated LS174T cells, was not significantly increased overall. No significant enhancement in the expression of three tumor-associated antigens (880364, NRCO-4, and ING-1) and the intercellular adhesion molecule-1 (ICAM-1) antigen on four human cancer cell lines was observed following in vitro exposure to levamisole. We conclude that levamisole is not a potent modulator of the immune parameters we examined, and that the mechanism behind the unique clinical interaction between levamisole and 5-fluorouracil in colorectal carcinoma remains to be identified.
