We investigated the effects of tumor necrosis factor (TNF) alpha, interferon (IFN) gamma and interleukin-2 (IL-2) on the mdr1 gene expression in four human colon carcinoma cell lines (Lo Vo, HT 115, SW 480, and LS 174T) at different times (8, 24, 48, and 72 h). We found no significant changes in mdr1 expression after 8 h and 24 h of cytokine treatment in all four lines. After 48 h and 72 h, however, a marked reduction of mdr1 expression in Lo Vo, HT 115, and SW 480 cells and an unaffected expression in LS 174T cells was observed. We examined whether the cytokine-mediated reduction of mdr1 expression correlates to the multidrug resistance (MDR) phenotype. In those cell lines showing a decreased mdr1 expression after a long-term cytokine pretreatment we found a dramatic enhancement of cytotoxicity of the MDR relevant drugs vincristine and doxorubicin, whereas LS 174T cells remained resistant. By contrast, the simultaneous application of cytokines and cytostatics caused no additive or synergistic effects. We conclude that in certain colon carcinoma cell lines a decreased mdr1 expression caused by prolonged cytokine pretreatment correlates with an enhanced cytotoxicity of drugs susceptible to MDR as an MDR-overcoming effect.