THE DEVELOPMENT OF DRUG-RESISTANCE BY TUMOR-CELLS IN-VITRO IS ACCOMPANIED BY THE DEVELOPMENT OF SENSITIVITY TO SELENITE

The effects of selenite on cell viability and proliferation in a line of drug-sensitive human ovarian tumor (A2780) cells were compared with its effects on a melphalan-resistant derivative of these cells (A2780 -ME) which had been developed in vitro (Hamilton et al. (1985) Biochem ical Pharmacol., 34, 2583-2586). With the A2780-ME cells there was a 5 0% decrease in the number of viable cells (i.e. which exclude Trypan B lue dye) after exposure to less than 100 mu M selenite for 6 h. In con trast, exposure to more than 300 mu M selenite was required to achieve the same effect in the parent line. Similarly, exposure to 10 mu M se lenite resulted in a 50% decrease in A2780-ME cell proliferation, wher eas this treatment had only a small inhibitory effect on proliferation of the parent cells. Thus, the development of melphalan resistance in vitro was accompanied by the development of selenite sensitivity. Pre -exposure of the two cell types to buthionine sulfoximine eliminated t he difference in their intracellular glutathione levels, as well as mo st of their differential sensitivity to selenite. Furthermore, the two cell types did not exhibit a difference in sensitivity to selenodigtu tathione, the product of the reaction of selenite with glutathione. Th us, the increase in intracellular glutathione, which has been shown to be responsible for the development of drug resistance in these cells is also responsible for the development of selenite sensitivity.