Cytoplasmic receptor levels and glucocorticoid response in human lymphoblastoid cell lines

Abstract

Summary.-The cytolethal response to treatment with prednisolone was investigated in vitro in eight human lymphoblastoid cell lines containing varying concentrations of specific cytoplasmic glucocorticoid receptors. A similar response was observed in seven of the lines irrespective of their concentration of cytoplasmic receptors, and pharmacological doses of steroid, well above those required to saturate receptors in cell-free extracts, were required for a massive lethal response. One cell line derived from Burkitt's lymphoma was refractory to lethal effects even with pharmacological doses of steroid.A similar unresponsiveness to the cytolethal effect of prednisolone in vitro was observed in fresh lymphoblasts derived from patients with acute lymphoblastic leukaemia despite evidence of a satisfactory clinical response to therapy which included steroid. The resistance of human lymphoblastoid cells to treatment with glucocorticoids in vitro may result from a defect in activation subsequent to the binding of steroid to cytoplasmic receptors.

Cytolethal effects of glucocorticoids in human lymphoblastoid cell lines

“…These studies confirm our previous observation (Bird et al, 1975) that lethal effects in human lymphoblastoid cell lines and in fresh peripheral blood lymphoblasts from patients with acute lymphoblastic leukaemia can only be achieved in vitro with doses of glucocorticoids which greatly exceed normal physiological and pharmacological levels. Assuming that equilibration of steroids within the fluid compartments of the body is equal and non-concentrative, the highest pharmacological doses of glucocorticoids employed in clinical practice (100-500 mg/mz body surface) would achieve peak intracellular concentrations around 1-5 x lo-% Maximum physiological plasma steroid levels are generally considered to be about lO-6-lO-7~, much of which is probably bound to plasma corticosteroid binding globulin (transcortin) (Burton and Westphal, 1972).…”

“…Specific cytoplasmic glucocorticoid receptors have been detected also in freshly isolated lymphoblasts from patients with acute lymphoblastic leukaemia and responsiveness in vivo to drug combinations, which included glucocorticoids, appeared to correlate with the concentration of cytoplasmic steroid receptors (Lippman et al, 1973). However, studies with human lymphoblastoid cell lines (Gailani et al, 1973;Lippman, Perry and Thompson, 1974;Bird et al, 1975) have failed to confirm any direct association between cytoplasmic receptor levels and glucocorticoid responsiveness in vitro. Furthermore, to obtain lethal effects we had to use doses of glucocorticoids which greatly exceeded both physiological steroid levels and the binding capacity of receptors in cytosol extracts of cells.…”

Glucocorticoid binding and cytolethal responsiveness of hairy-cell and chronic lymphocytic leukaemia

“…Substantial clinical responses are obtained in many CLL patients with doses of glucocorticoid that produce only minor cytolethal responses in vitro. Glucocorticoids are known to have wide ranging and complex effects on many cells and tissues throughout the body and it is possible that these may play a contributory part in determining clinical responses in leukaemia in addition to any direct cytolethal hormone effect (Bird 1979). The demonstration of substantial levels of glucocorticoid binding in circulating leukaemic cells of all HCL patients studied in this series suggests that HCL and CLL could respond in similar fashion.…”

Spinal Compression Due to Burkitt Lymphoma in a Newly Diagnosed HIV-infected Child

“…23,24 This illustrates the need to monitor closely the therapeutic effect of steroids in medullar compression syndromes of unknown origin to introduce other therapies if no evidence of progress with steroids is noted.…”