Moody T W, Korman L Y
Department of Biochemistry, George Washington University School of Medicine and Health Sciences, Washington.
Ann N Y Acad Sci. 1988;547:351-9. doi: 10.1111/j.1749-6632.1988.tb23902.x.
High levels of BN/GRP are present in classic SCLC and lung carcinoids, whereas BN immunoreactivity is absent in variant SCLC, adenocarcinoma, large cell carcinoma, squamous cell carcinoma, and mesothelioma cell lines. BN-like peptides are secreted from classic SCLC into the tissue culture medium. The secretion rate of BN-like peptides from cell line NCI-H345 was increased 3-fold by VIP (1 microM). Also, VIP increased the cAMP levels in cell line NCI-H345 by an order of magnitude. Therefore, SCLC cells have functional VIP receptors which regulate the secretion of BN-like peptides. Also, SRIF (100 nM) inhibits the VIP-stimulated increase in cAMP levels and secretion rate of BN-like peptides from SCLC cells. Because BN stimulates colony formation, VIP and/or SRIF may be able to alter the growth of SCLC cells. BN-like peptides are secreted from SCLC cells into the plasma. The levels of BN immunoreactivity in the plasma of SCLC patients with extensive disease is 2- to 40-fold greater than that of patients with limited disease. Secretin infusion into patients with extensive disease produces a transient increase (7-fold) in the plasma concentration of BN-like peptides. BN-like peptides are also present in the CSF of SCLC patients. When released from SCLC cells, BN-like peptides may interact with cell surface receptors. [Tyr4]BN binds with high affinity (Kd = 0.5 nM) to a single class of sites (1500/cell) on cell line NCI-H345. The carboxyl terminus of BN or GRP is essential for high-affinity binding activity. BN-like peptides elevate cytosolic Ca2+ levels as a result of increased phosphatidylinositol turnover. The putative BN receptor antagonist [D-Arg1, D-Pro2, D-Trp7,9, Leu11]substance P inhibits high-affinity [Tyr4]BN binding, the ability of BN to elevate cytosolic Ca2+ levels, and colony formation of SCLC cells. Therefore, BN receptor antagonists may serve as useful agents to inhibit the growth of SCLC.
高水平的BN/GRP存在于典型的小细胞肺癌（SCLC）和肺类癌中，而在变异型SCLC、腺癌、大细胞癌、鳞状细胞癌和间皮瘤细胞系中不存在BN免疫反应性。BN样肽从典型的SCLC分泌到组织培养基中。VIP（1微摩尔）使细胞系NCI-H345中BN样肽的分泌率增加了3倍。此外，VIP使细胞系NCI-H345中的cAMP水平提高了一个数量级。因此，SCLC细胞具有功能性VIP受体，可调节BN样肽的分泌。此外，生长抑素（SRIF，100纳摩尔）抑制VIP刺激的SCLC细胞cAMP水平升高和BN样肽分泌率增加。由于BN刺激集落形成，VIP和/或SRIF可能能够改变SCLC细胞的生长。BN样肽从SCLC细胞分泌到血浆中。广泛期SCLC患者血浆中BN免疫反应性水平比局限期患者高2至40倍。向广泛期患者输注促胰液素会使血浆中BN样肽浓度短暂升高（7倍）。BN样肽也存在于SCLC患者的脑脊液中。当从SCLC细胞释放时，BN样肽可能与细胞表面受体相互作用。[Tyr4]BN以高亲和力（解离常数Kd = 0.5纳摩尔）与细胞系NCI-H345上的一类位点（每个细胞1500个）结合。BN或GRP的羧基末端对于高亲和力结合活性至关重要。由于磷脂酰肌醇周转率增加，BN样肽会提高胞质Ca2 +水平。推定的BN受体拮抗剂[D-Arg1, D-Pro2, D-Trp7,9, Leu11]P物质抑制高亲和力的[Tyr4]BN结合、BN提高胞质Ca2 +水平以及SCLC细胞集落形成的能力。因此，BN受体拮抗剂可能是抑制SCLC生长的有用药物。
