Phenothiazines cause a shift in the cAMP dose-response: selection of resistant variants in a murine thymoma line.
Phenothiazines cause a shift in the cAMP dose-response: selection of resistant variants in a murine thymoma line.
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吩噻嗪引起 cAMP 剂量反应的转变：小鼠胸腺瘤系中耐药变异的选择。
DOI：
10.1002/jcp.1041190118
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发表时间：
1984
影响因子：
5.6
通讯作者：
Dalton,DK
中科院分区：
文献类型：
--
作者：
Gruol,DJ;Dalton,DK
环 AMP 和糖皮质激素各自促进小鼠淋巴细胞系 WEHI-7.1 (W7) 中的细胞溶解反应。几种能够干扰多种钙调节功能的精神药物可以增强对二丁酰环 AMP (dbcAMP) 的敏感性，但不能增强对地塞米松的敏感性。我们表征了 W7 细胞对吩噻嗪三氟拉嗪 (TFP) 的反应，发现 TFP 浓度使生长速率降低两倍，使 dbcAMP 的剂量反应变化约十倍。磷酸二酯酶抑制剂甲基异丁基黄嘌呤 (MIX) 也出现了类似但较小的变化。 TFP 和 MIX 对 dbcAMP 反应的影响是相加的，表明 TFP 可能会增加 W7 细胞对 cAMP 依赖性蛋白激酶作用的敏感性，并且敏感性的增加可能是由于 cAMP 和钙共同调节的裂解功能改变所致。 TFP 引起的对 dbcAMP 剂量反应的变化提供了一种选择方法，以获得变异体，这些变异体对 dbcAMP、TFP 或两种药物的组合的反应能力发生了改变。经过诱变和组合药物选择后获得的品系中，有 8 个品系（共 36 个）已被部分表征。这揭示了几种新表型的存在。大多数在 TFP 存在的情况下对 dbcAMP 的反应发生改变，并且可能代表以前未观察到的变异。
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.