Isolation and characterization of lymphosarcoma P1798 variants selected for resistance to the cytolytic effects of glucocorticoids in vivo and in culture

Abstract

Clonal subpopulations of lymphosarcoma P1798 have been subjected to glucocorticoid selection in vivo and in culture and the glucocorticoid binding and responsiveness of the resistant variants have been compared with those of the parental lines. Cell populations that are resistant to the cytolytic effects of glucocorticoids in vivo exhibit a slightly reduced level of glucocorticoid binding, although nuclear translocation of the hormone-receptor complex is not reduced. Sensitive and resistant tumors exhibit similar kinetics of hormone uptake and dissociation following a single injection of dexamethasone. Selection for glucocorticoid resistance in vivo does not result in an increase in the modal number of chromosomes. Cells that are resistant to the cytolytic effects of glucocorticoids in vivo are completely sensitive to the antiproliferative effects of glucocorticoids in culture. Moreover, dexamethasone increases the expression of mouse mammary tumor provirus in cytolysis-resistant and sensitive cells both in vivo and in culture. Selection for glucocorticoid resistance in culture yields variants with decreased glucocorticoid binding and/or nuclear translocation of the hormone-receptor complex. These cells appear to express classical receptor-defective phenotypes. Nevertheless, cells that are resistant to glucocorticoids in culture undergo cytolysis when treated with glucocorticoids in vivo. These data indicate that, under certain circumstances, different mechanisms may be involved in loss of glucocorticoid responsiveness in vivo and in culture.