ESTABLISHMENT BY ADRIAMYCIN EXPOSURE OF MULTIDRUG-RESISTANT RAT ASCITES HEPATOMA AH130 CELLS SHOWING LOW DT-DIAPHORASE ACTIVITY AND HIGH CROSS-RESISTANCE TO MITOMYCINS

A resistant subline (AH130/5A) selected from rat hepatoma AH130 cells after exposure to adriamycin (ADM) showed remarkable resistance to mul tiple antitumor drugs, including mitomycin C (MMC) and porfiromycin (P FM). PFM, vinblastine (VLB), and ADM accumulated in AH130/5A far less than in the parent AH130 (AH130/P) cells. AH130/5A cells showed overex pression of P-glycoprotein (PGP), an increase in glutathione S-transfe rase activity, and a decrease in DT-diaphorase and glutathione peroxid ase activity. The resistance to MMC and VLB of AH130/5A cells was part ly reversed by H-87, an inhibitor of PGP. Buthionine sulfoximine, an i nhibitor of glutathione synthase, did not affect the action of MMC. te rt-Butylhydroquinone induced DT-diaphorase activity, increased PFM upt ake, and enhanced the growth-inhibitory action of MMC in AH130/5A cell s. Dicumarol, an inhibitor of DT-diaphorase, decreased PFM uptake and reduced the growth-inhibitory action of MMC in AH130/P cells. These re sults indicated that the adriamycin treatment of hepatoma cells caused multifactorial multidrug resistance involving a decrease in DT-diapho rase activity.