SECOND MESSENGER AND RECEPTOR SYSTEMS IN HUMAN SCLC

小细胞肺癌（SCLC）细胞系的既往研究 已经证明，胃泌素释放肽（GRP）， 蛙皮素的哺乳动物对应物，以 SCLC细胞系的显著部分。 为了评估它在导致 自分泌刺激，最初的实验试图 证明与SCLC膜组分特异性结合， 小小的成功 因此，定义快速生理学的努力 对GRP作出了回应。 这些研究证明 显然，在5/11的SCLC细胞系中，有证据表明， GRP或蛙皮素刺激后的钙动员。 该作用的构效关系符合雅阁 与肠、脑和前叶中GRP受体的预期结果一致， 垂体细胞 进一步的研究集中在 这种对磷酸肌醇代谢的反应。 在SCLC细胞中 对GRP有活跃反应的细胞内 钙，有证据表明增加肌醇1，4，5 在几秒钟内添加蛙皮素同源物。 钙的动员和磷酸肌醇的周转 被霍乱毒素和活性佛波醇酯抑制。 在 百日咳毒素的存在，也有一个不太完整的 刺激磷酸肌醇周转。 在推论研究中， 结果表明，具有最佳反应的细胞系 蛙皮素显示L-myc和prepro的组成性表达， 不表达c-或N-myc的GRP。 相反，细胞系 没有对蛙皮素反应的证据， C-myc表达。 这些研究表明，一个渐进的恶性顺序， 并且在SCLC细胞系中可以定义不同的表型。 一 大多数"分化的"细胞系是那些产生和 对GRP有反应，也产生L-myc。 较少分化 细胞系既不产生也不响应GRP，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 阻断涉及GRP的潜在自分泌回路可能是最重要的 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.