LEVAMISOLE EFFECTS ON MAJOR HISTOCOMPATIBILITY COMPLEX AND ADHESION MOLECULE EXPRESSION AND ON MYELOID CELL-ADHESION TO HUMAN COLON-TUMOR CELL-LINES

Background: The drug levamisole has been successfully used in combinat ion with fluorouracil to increase the disease-free interval and surviv al of patients who have undergone surgical resection of Dukes' stage C colon cancer. Levamisole is thought to affect the host immune respons e. Several recent studies have examined its effect on the expression o f major histocompatibility complex (MHC) class I molecules, but the re sults have been inconsistent. An equally important requirement for a h ost cellular immune response is the adhesion of leukocytes to tumor ce lls. The latter may be required for cell-mediated antitumor cytotoxic responses. Purpose: We evaluated the ability of levamisole to affect t he expression of MHC class I molecules and cell-adhesion molecules and determined whether levamisole could affect leukocyte adhesion to tumo r cells that had been treated with the drug. Methods: A panel of four human colon tumor cell lines (HT-29, SW-620, HCT-15, and LoVo), A-375 human melanoma cells, and human umbilical vein endothelial cells (HUVE C) were cultured in the presence of levamisole and examined by solid-p hase enzyme immunoassay to determine the level of expression of MHC cl ass I, intercellular adhesion molecule 1 (ICAM-1), vascular cell-adhes ion molecule-1 (VCAM-1), leukocyte integrin VLA-4, and lymphocyte-func tional antigen (LFA-1) molecules. Adhesion of HL-60 and THP-1 myeloid cells to tumor cells was also evaluated. Tumor necrosis factor (TNF) a t 10 ng/mL was used as a positive control for increasing adhesion mole cule expression and cell-cell adhesion. The statistical significance o f differences in cell surface molecule expression and functional adhes ion between treated and control cells were tested by use of analysis o f variance and the two-tailed Dunnett's test. Results: Treatment with levamisole (0.1 and 1 mu g/mL) caused the levels of MHC class I expres sion to increase approximately threefold above control levels on HCT-1 5 and LoVo colon tumor cells (P<.05 in each case) compared with untrea ted cells, caused minimal increases on HT-29 cells (to 1.5 times contr ol levels), but caused no significant increases on SW-620 colon tumor or A-375 melanoma cells, The HCT-15 and LoVo colon tumor cells had ver y low basal MHC expression. Levamisole (1 mu g/mL) increased VCAM-1 ex pression on HT-29 and SW-620 colon tumor cells to 4.3 and 2.4 times (P <.05 in each case) control levels, respectively, doubled ICAM-1 expres sion on HT-29 cells (P<.05), and increased LFA-1 expression on HT-29, LoVo, and A-375 cells to 2.1, 3.2, and 1.8 (P<.05 in each case) times control levels, respectively. TNF (10 ng/mL) was used as a positive co ntrol and yielded increased expression of MHC class I molecules on the HT-29, LoVo, SW-620, and HCT-15 cells (2.5, 7.8, 1.9, and 4.8 times c ontrol levels, respectively; P<.05 in each case). TNF increased VCAM-1 expression to 4.2 times the vehicle-treated control levels (P<.05) on HT-29 cells and increased ICAM-1 expression on HT-29, LoVo, and SW-62 0 cells (8.4, 1.8, and 1.9 times vehicle control levels, respectively; P<.05 in each case). THP-1 and HL-60 cells demonstrated increased adh esion to Levamisole-treated HT-29 colon tumor cells. HL-60 cells also exhibited increased levamisole-mediated adherence to LoVo and HCT-15 c ells. Adherence by THP-1 was significantly improved after levamisole t reatment of the HUVEC, SW-620, and A-375 cells (P<.05 in each case). C onclusions: Levamisole can directly affect the expression and function of molecules that are engaged in cell-cell recognition and signaling on the surfaces of some tumor cell lines. However, no consistent patte rn between cell-adhesion molecule expression, cell-cell adhesion, or l evamisole concentration could be discerned.