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Isolation and Characterization of a Rat Liver Epithelial Cell Line Resistant to the Antiproliferative Effects of Transforming Growth Factor ß (Type 1)

Laboratory of Experimental Carcinogenesis, Division of Cancer Etiology, National Cancer Institute, NIH, Bethesda, Maryland 20892

Rat liver epithelial cells resistant to the growth-inhibitory effects of transforming growth factor ß₁ (TGF-ß₁) were isolated after 3 h exposure to 1.5 µg/ml of N-methyl-N'-nitro-N-nitrosoguanidine followed by continuous treatment with 1 ng/ml TGF-ß₁ for 6 weeks. In comparison to the parental or N-methyl-N'-nitro-N-nitrosoguanidine-exposed rat liver epithelial cells (concentration causing 50% inhibition of the rate of DNA synthesis, 0.25 ng/ml), these cells were 10-fold more resistant to the antiproliferative effects of TGF-ß₁ and exhibited resistance to growth inhibition by a highly purified liver-derived growth inhibitor, recombinant human tumor necrosis factor, and transforming growth factor ß₂. Single cell cloning of these resistant cells led to the isolation of a nontransformed clonal cell population (clone 11) which maintained stable resistance in the absence of TGF-ß₁ treatment. Binding of ¹²⁵I-labeled TGF-ß₁ to rat liver epithelial cells and clone 11 cells was similar. Clone 11 cells exhibited a 5–10-fold resistance to the cytotoxins Adriamycin and vinblastine as assessed by a clonogenic assay. This drug resistance was accompanied by an increase in the steady state levels of the mRNAs for multidrug resistance gene (MDR-1), glutathione S-transferase-P, TGF-ß₁, and c-myc genes. The data presented here suggest an association between resistance to the growth-inhibitory effects of TGF-ß₁-and MDR-1-mediated multidrug resistance.

¹ To whom requests for reprints should be addressed, at Laboratory of Experimental Carcinogenesis, National Cancer Institute, Building 37, Room 3C28, NIH, Bethesda, MD 20892.

Received 11/ 3/89. Revised 2/26/90.