INFLUENCE OF CYTOKINES ON MDR1 EXPRESSION IN HUMAN COLON-CARCINOMA CELL-LINES - INCREASED CYTOXICITY OF MDR RELEVANT DRUGS

We investigated the effects of tumor necrosis factor (TNF) alpha, inte rferon (IFN) y and interleukin-2 (IL-2) on the mdr1 gene expression in four human colon carcinoma cell lines (LoVo, HT 115, SW 480, and LS 1 74T) 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 i n all four lines. After 48 h and 72 h, however, a marked reduction of mdr1 expression in LoVo, HT 115, and SW 480 cells and an unaffected ex pression in LS 174T cells was observed. We examined whether the cytoki ne-mediated reduction of mdr1 expression correlates to the multidrug r esistance (MDR) phenotype. In those cell lines showing a decreased mdr 1 expression after a long-term cytokine pretreatment we found a dramat ic enhancement of cytotoxicity of the MDR relevant drugs vincristine a nd doxorubicin, whereas LS 174T cells remained resistant. By contrast, the simultaneous application of cytokines and cytostatics caused no a dditive or synergistic effects. We conclude that in certain colon carc inoma cell lines a decreased mdr1 expression caused by prolonged cytok ine pretreatment correlates with an enhanced cytotoxicity of drugs sus ceptible to MDR as an MDR-overcoming effect.