Search

The effects of the membrane-stabilizing agent, alpha-tocopherol (25 microg/ml), on the chemosensitizing interactions of cyclosporin A (5 microg/ml), verapamil (2 microg/ml), clofazimine (1 microg/ml), B669 (0.5 microg/ml) and GF120918 (0.015 microg/ml) with a P-glycoprotein-expressing human lung cancer cell line (H69/LX4) have been investigated in vitro. In an assay of cell proliferation, all the chemosensitizing agents restored the sensitivity of H69/LX4 cells to doxorubicin and vinblastine. The inclusion of alpha-tocopherol (25 microg/ml) antagonized the multidrug-resistance (MDR)-modifying activity of all five chemosensitizing agents, effectively preventing restoration of sensitivity to both doxorubicin and vinblastine in H69/LX4 cells.

Differential expression of a permeability glycoprotein (P-gp) in human myeloleukaemia K562 cells grown in the presence of the anti-cancer drug, doxorubicin, gave rise to subclones with varying degrees of resistance to other anti-tumour drugs such as vinblastine and daunorubicin. Subclones K562/MMB, MMG and MMF were produced from the parental (K562/P) cell line via limiting dilution and their MDR nature confirmed with flow cytometry using an MRK 16 monoclonal antibody directed at a surface epitope of the P-gp pump. The pattern of increasing P-gp expression in the series K562/P, MMF, MMG and MMB was paralleled by increasing resistance to vinblastine and daunorubicin. When the subclones were pre-incubated with the chemosensitizing drugs clofazimine and B669, a pattern of increasing reversal of resistance to vinblastine and daunorubicin was seen in the series K562/P, MMF, MMG and MMB.

The potential of the riminophenazine agents clofazimine and B669, at therapeutically relevant concentrations, to reverse P-glycoprotein-mediated multidrug-resistance (MDR) in a human lung cancer cell line (H69/LX4) has been investigated in vitro. Cyclosporin A, a well-documented MDR-modifying agent, was included for comparison. Clofazimine, B669 and cyclosporin A at minimally cytotoxic concentrations of 1, 0.5 and 5 micrograms/ml, respectively, were equally effective in restoring sensitivity to vinblastine, doxorubicin, daunorubicin and mitomycin C in the H69/LX4 cell line. All three chemosensitizing agents also increased the accumulation of [14C]vinblastine by H69/LX4 cells. Riminophenazines, which are relatively non-toxic, non-carcinogenic and non-myelosuppressive agents, are promising contenders for evaluation in experimental and clinical oncology as modulators of acquired MDR.