Phenothiazines cause a shift in the cAMP dose-response: selection of resistant variants in a murine thymoma line

Cyclic AMP and glucocorticoid hormones each promote a cytolytic response in the murine lymphoid cell line WEHI-7.1 (W7). The sensitivity to dibutyryl cyclic AMP (dbcAMP), but not dexamethasone, can be enhanced by several psychotropic drugs that have the capacity to interfere with a variety of calcium-regulated functions. We have characterized the response of W7 cells to the phenothiazine trifluoperazine (TFP) and found that TFP concentrations, which decreased the growth rate by twofold, shifted the dose response to dbcAMP approximately tenfold. A similar but smaller shift was seen with the phosphodiesterase inhibitor methylisobutylxanthine (MIX). The effects of TFP and MIX on the dbcAMP response were additive, suggesting that TFP may act to increase the sensitivity of W7 cells to the action of cAMP-dependent protein kinase, and that the increased sensitivity may be due to altered lytic functions coregulated by both cAMP and calcium. The change in the dose response to dbcAMP caused by TFP provided a means of selection to obtain variants that were altered in their capacity to respond to dbcAMP, TFP, or the combination of the two drugs. Eight (out of 36) of the lines that were obtained after a mutagenesis and combined drug selection have been partially characterized. This has revealed the existence of several new phenotypes. Most have an altered response to dbcAMP in the presence of TFP and are likely to represent variants that have not been observed before.