CYCLOSPORINE-A AND FK506 REVERSE ANTHRACYCLINE RESISTANCE BY ALTERINGTHE CELL-CYCLE

We investigated the effect of cyclosporin A (CsA) or FK506 on the cyto toxicity of anthracyclines against a human laryngeal cancer cell line, KB cells, and a multidrug resistance cell line, VJ-300 cells. CsA and FK506 enhanced the cytotoxicity of anthracyclines, especially in the VJ-300 cells, The intracellular concentrations of epirubicin (EPIR), d aunomycin (DAI), adriamycin (ADM) and THP-adriamycin (THP) were increa sed by the addition of CsA or FK506 in VJ-300, but not in KB cells, Th e intracellular accumulation of EPIR was most increased when CsA or FK 506 was concomitantly administered with the drug. We also asked whethe r CsA or FK506 might influence the cycle of KB or VJ-300 cells, The po pulation of cells in each phase of the cell cycle was little changed i n both KB and VJ-300 cells when 0.3 mu M ADM was administered for 24 h , Both CsA and FK506 significantly increased the ADM-induced accumulat ion of VJ-300 cells in G(2)M phase, in comparison with findings with K B cells, Thus, the reversal of MDR by CsA or FK506 is related to incre ased intracellular concentrations of cytotoxic drugs end, as a result, the increased G(2)M accumulates in MDR cells, Among of antrhacyclines , EPIR was most effective when concomitantly combined with CsA or FK50 6 in VJ-300 cells.