INHIBITION OF P-GLYCOPROTEIN-DEPENDENT MULTIDRUG-RESISTANCE BY AN ISOQUINOLINESULFONAMIDE COMPOUND H-87 IN RAT ASCITES HEPATOMA AH66 CELLS

The effects of compound, H-87, on naturally acquired multidrug-resista nce (MDR) in rat hepatoma AH66 cells were examined, AH66 cells were hi ghly resistant to vinblastine, SN-38, an active camptothecin analog, a driamycin, and etoposide, compared with the sensitive variant AH66F ce lls, Although H-87 hardly affected the sensitivities to antitumor agen ts of AH66F cells, this compound completely inhibited the resistance t o vinblastine, moderately inhibited the resistance to SN-38 and adriam ycin and had little effect on etoposide, mitomycin C, cisplatin, and 5 -fluorouracil. H-87 significantly decreased the efflux of vinblastine from the resistant cells and increased the drug accumulation, SN-38 an d adriamycin also exhibited a weak but significant increase in vinblas tine accumulation in AH66 cells, H-87 inhibited [H-3]azidopine-photola beling to 160 kDa P-glycoprotein in the plasma membrane of AH66 cells, as reported in acquired MDR leukemic cells, Consequently, the MDR-ove rcoming effect of H-87 seems to be due to its direct inhibition of the binding of antitumor agents on P-glycoprotein in the plasma membrane.