Establishment by Adriamycin Exposure of Multidrug‐resistant Rat Ascites Hepatoma AH130 Cells Showing Low DT‐diaphorase Activity and High Cross Resistance to Mitomycins

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Abstract
A resistant subline (AH130/5A) selected from rat hepatoma AH130 cells after exposure to adriamycin (ADM) showed remarkable resistance to multiple antitumor drugs, including mitomycin C (MMC) and porflromycin (PFM). PFM, vinblastine (VLB), and ADM accumulated in AH130/5A far less than in the parent AH130 (AH130/P) cells. AH130/5A cells showed overexpression of P‐glycoprotein (PGP), an increase in glutathione S‐transferase activity, and a decrease in DT‐diaphorase and glutathione peroxidase activity. The resistance to MMC and VLB of AH130/5A cells was partly reversed by H‐87, an inhibitor of PGP. Buthionine sulfoximine, an inhibitor of glutathione synthase, did not affect the action of MMC. tert‐Butylhydroquinone induced DT‐diaphorase activity, increased PFM uptake, and enhanced the growth‐inhibitory action of MMC in AH130/5A cells. Dicumarol, an inhibitor of DT‐diaphorase, decreased PFM uptake and reduced the growth‐inhibitory action of MMC in AH130/P cells. These results indicated that the adriamycin treatment of hepatoma cells caused multifactorial multidrug resistance involving a decrease in DT‐diaphorase activity.