SECOND MESSENGER AND RECEPTOR SYSTEMS IN HUMAN SCLC

小细胞肺癌(SCLC)细胞系的研究进展 已证明胃泌素释放肽(GRP)、 哺乳动物中的蛙皮素，在一种 相当一部分的小细胞肺癌株系。以评估其在导致 自分泌刺激，最初的实验试图 展示与SCLC膜组分的特异性结合， 小小的成功。因此，努力定义快速生理学 对GRP进行了答复。这些研究表明 显然，在测试的5/11小细胞肺癌细胞系中，有证据表明 GRP或蛙皮素刺激后的钙动员。 该作用的构效关系一致 预计肠道、脑和前部的GRP受体也是如此 脑垂体细胞。进一步的研究集中在两者之间的关系。 这种对肌醇磷酸代谢的反应。在SCLC单元中 对GRP反应迅速且细胞内含量增加的品系 钙，有证据表明肌醇1，4，5增加 三磷酸在添加蛙皮素同系物后的几秒钟内。 钙和肌醇磷酸周转的动员 被霍乱毒素和活性佛波酯抑制。在 百日咳毒素的存在也不太完整 刺激肌醇磷酸盐周转。在推论研究中 证明了对病毒反应最好的细胞系 蛙皮素显示L-myc和前蛋白的组成性表达 不表达c-myc或N-myc的GRP。相比之下，细胞系 在没有对蛙皮素反应的证据的情况下，有结构性的N-或 C-myc的表达。 这些研究表明，一种逐渐恶性的顺序 在小细胞肺癌细胞系中可以定义不同的表型。一个 大多数“分化”的细胞系将是那些产生和 响应GRP，也产生L-myc。差异化程度较低的 细胞株对GRP既不产生也不反应，并表达 富含c-或N-myc。Grp(+)、L-myc(+)、c-myc(-)和N- MYC(-)细胞系将代表那些努力 阻止涉及GRP的潜在自分泌循环可能是最 成功。

Previous studies with small cell lung cancer (SCLC) cell lines have demonstrated that gastrin-releasing peptide (GRP), the mammalian counterpart to bombesin, is expressed in a significant fraction of SCLC lines. To assess its role in causing autocrine stimulation, initial experiments attempted to demonstrate specific binding to SCLC membrane fractions, with little success. Accordingly, efforts to define rapid physiologic responses to GRP were undertaken. These studies demonstrated clearly that in 5/11 SCLC cell lines tested there was evidence of calcium mobilization following GRP or bombesin stimulation. The structure-activity relationship of this effect was in accord with that expected for GRP receptors in gut, brain, and anterior pituitary cells. Further studies focused on the relationship of this response to inositol phosphate metabolism. In a SCLC cell line with a brisk response to GRP with increased intracellular calcium, there was evidence of increased inositol 1,4,5 trisphosphate within seconds of addition of bombesin congeners. Both the mobilization of calcium and inositol phosphate turnover were inhibited by cholera toxin and active phorbol esters. In the presence of pertussis toxin there was also a less complete stimulation of inositol phosphate turnover. In corollary studies it was demonstrated that the cell lines with the best response to bombesin showed constitutive expression of L-myc and prepro GRP without expression of c- or N-myc. In contrast, cell lines without evidence of response to bombesin had constitutive N- or C-myc expression. These studies suggest that an order of progressively malignant and distinct phenotypes can be defined in SCLC cell lines. A most "differentiated" cell line would be those which produce and respond to GRP, and also produce L-myc. A less differentiated cell line would neither produce nor respond to GRP and express abundant c- or N-myc. GRP (+), L-myc (+), c-myc (-), and N- myc (-) cell lines would represent those in which an effort to block a potential autocrine loop involving GRP might be most successful.