Cultured human epithelial cells (HE), grown as monolayers, acquired resistance to otherwise lethal concentrations (300 mumol/l, culture medium) of sodium aurothiomalate during five months' exposure to stepwise increased concentrations of the drug. The resistance acquired was shown by exposure to drug concentrations ranging from 25 to 300 mumol/, resulting in 100% of the resistant cells (HeMyo) surviving compared with controls. Only 13% of the sensitive parent cells survived when exposed to 300 mumol/l for four days. The HeMyo cells were also resistant to the antiproliferative effects of equimolar concentrations of thiomalic acid without gold. The cytosolic gold concentration and the association of 199Au with cytosolic proteins after gel filtration were similar in both cell lines after sodium aurothiomalate exposure to the exponentially growing cells. No synthesis of gold binding proteins of metallothionein character was observed in the HEMyo cells. The concentration of free thiomalate in the sonicates and cytosols of the HeMyo cells was decreased to 25-30% of the concentration found in the HE cells. Comparison with previous data for the cytosolic concentration of total thiomalate in the HE cells suggests that most of the cytosolic thiomalate present was free thiomalate. We conclude that the cells can develop resistance to the antiproliferative effect of sodium aurothiomalate, and that the resistance may be due to their capacity to maintain low concentrations of free thiomalate in the sonicates and cytosols. The results support previous findings that sodium aurothiomalate appears to dissociate within cells.
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