SECOND MESSENGER AND RECEPTOR SYSTEMS IN HUMAN SCLC

以前对小细胞肺癌（SCLC）细胞系的研究表明， 证明了胃泌素释放肽（GRP），哺乳动物 蛙皮素的对应物，在 SCLC线路。 为了评估其在引起自分泌刺激中的作用， 最初的实验试图证明特异性结合 SCLC膜组分，但收效甚微。 因此，努力 以确定对GRP的快速生理反应。 这些研究清楚地表明，在5/11的SCLC细胞系中， 测试有证据表明，钙动员后，GRP或 蛙皮素刺激 这种结构与活性的关系 作用与对肠道中GRP受体预期的雅阁， 脑和垂体前叶细胞。 进一步的研究集中在 这种反应与磷酸肌醇代谢的关系。 在SCLC细胞系中，对GRP的反应活跃， 细胞内钙，有证据表明增加肌醇 在添加蛙皮素的几秒钟内1，4，5三磷酸盐 同类物。 钙和磷酸肌醇的动员 霍乱毒素和活性佛波醇酯抑制周转。 在百日咳毒素的存在下， 刺激磷酸肌醇周转。 在推论研究中， 结果表明，对以下物质具有最佳应答的细胞系 蛙皮素呈组成型表达，L-myc和prepro GRP 而不表达c-或N-myc。 相反，没有 对蛙皮素反应的证据具有组成性N-或c-myc 表情 这些研究表明，进行性恶性和 可以在SCLC细胞系中定义不同的表型。 一个最 “分化的”细胞系将是那些产生和响应 转化成GRP，并产生L-myc。 分化程度较低的细胞系 不会产生GRP，也不会对GRP产生反应，并表达丰富的c- 或N-myc。 GRP（+）、L-myc（+）、c-myc（-）和N-myc（-）细胞系 将代表那些试图阻止潜在的 涉及GRP的自分泌环可能是最成功的。

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.