Toxicity of Levamisole and 5-Fluorouracil in Human Colon Carcinoma Cells

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Abstract
The combination of 5-fluorouracil (5-FU) with the immunomodulator levamisole (Lev) has been clinically tested in patients with metastatic colorectal carcinoma and as adjuvant therapy following primary tumor surgery. In some studies in advanced disease, the addition of Lev to 5-FU improved the median duration of response; in the adjuvant setting, the combination was associated with improvement in the disease-free survival. We studied whether Lev was directly toxic to three human colorectal carcinoma cell lines (HCT 116, SNU-C4, and NCI-H630). We also evaluated the toxicity of Lev in combination with 5-FU in these three cell lines. Lev inhibited the growth of all three colorectal cell lines, but only at concentrations two logs above that achieved with a standard 150-mg oral dose of Lev. In cell growth studies, 500 and 1,000 μM Lev increased the toxicity of 5-FU in HCT 116 cells in an additive fashion. In clonogenic assays, continuous exposure to 10 or 100 μM Lev was minimally toxic and did not enhance the lethality associated with a 24-hour exposure to 5-FU in any of the cell lines. Lev alone at 1,000 μM decreased colony formation by 45% in HCT 116 cells. A combination of 1,000 μM Lev with 10 M 5-FU resulted in a decrease in HCT 116 colony formation from 54% to 6% of control levels. Continuous exposure of NCI-H630 cells to 500 μM Lev decreased colony formation to 76.5% of control levels; when Lev was combined with 50 μM 5-FU, colony formation was decreased from 59.5% to 27.5% of control levels. We conclude that at concentrations achievable with conventional doses of Lev, there was no evidence of direct toxicity in these colorectal cell lines. Furthermore, an additive interaction with 5-FU was evident only at suprapharinacologic doses of Lev. [J Nati Cancer Inst 81:1413–1417, 1989]