TOXINS TARGETED TO THE CELL MEMBRANE--DISRUPTION IN SIGNAL TRANSDUCTION

霍乱毒素（CT）抑制蛙皮素介导的信号的诱导 包括细胞内钙（[Ca 2 +]i）增加， 人小细胞肺癌磷脂酰肌醇代谢 细胞 这种效应是伴随着循环的增加而发生的。 毒素诱导的cAMP。 此外，毒素会抑制 携带CT受体神经节苷脂GM 1的SCLC细胞的生长。 最近，我们完成了CT对生长的影响的分析， 非小细胞肺癌（NSCLC）细胞的一系列。 相比之下 与CT介导的GM 1（+）SCLC细胞生长抑制相比，CT在 大约50%的NSCLC细胞系可以与NSCLC细胞结合， cAMP，但不降低细胞生长。这些结果提出了一种可能性 一小部分NSCLC细胞系对 增加cAMP。 在SCLC中，最近的实验表明， CT作用的结果是抑制GF膜脂质合成 包括磷脂酰肌醇、磷脂酰肌醇-4 '-磷酸（PIP）、 和磷脂酰肌醇-4，5-二磷酸（PIP）2。 这些结果将 这表明CT的作用是破坏蛙皮素所依赖的正常底物， 肽起启动信号转导的作用。 这些结果进一步 表明选择性递送激活腺苷酸CTA链 环化酶通过共价修饰的Gs，将是一个有用的手段， 靶向蛙皮素肽介导的信号转导。 此外，本发明还提供了一种方法， CT-B链可用于将新的毒性部分递送至 SCLC和NSCLC细胞的表面， 使毒素内化以观察特异性细胞毒性。 进一步 我们将致力于构建这样的分子， 破坏正常细胞膜的治疗策略 信号处理。 膜靶向毒素的临床应用是 正在进行的抗CD 22去糖基化临床试验中开发 B细胞淋巴瘤中的蓖麻毒素A链免疫毒素，以及抗CD-19 去糖基化蓖麻毒素A链构建。

Cholera toxin(CT) inhibits the induction of bombesin-mediated signals including increased intracellular calcium ([Ca2+]i) and phosphatidylinositol turnover in human small cell lung(SCLC) carcinoma cells. This effect occurs concomitant with the increase in cyclic AMP(cAMP) induced by the toxin. In addition, the toxin inhibits the growth of SCLC cells which bear the receptor for CT, the ganglioside GM1. Recently we have completed an analysis of the effect of CT on the growth of a series on non-small cell lung carcinoma(NSCLC) cells. In contrast to CT-mediated inhibition of growth of GM1(+) SCLC cells, CT in approximately 50% of NSCLC cell lines could bind to NSCLC cells, increase cAMP, yet not decrease cell growth. These results raise the possibility that a fraction of NSCLC cell lines are refractory to the consequences of increased cAMP. In SCLC, recent experiments indicate that a consequence of CT action is inhibition gf membrane lipid synthesis including phosphatidylinositol, phosphatidylinositol-4'-phosphate(PIP),l and phosphatidylinositol-4,5-bisphosphate(PIP)2. These results would suggest that CT acts to disrupt the normal substrate upon which bombesin peptides act to initiate signal transduction. These results further suggest that selective delivery of CT A chain, which activates adenylate cyclase through covalent modification of Gs, would be a useful means of targeting bombesin peptide mediated signal transduction. In addition, the CT-B chain could be used to deliver novel toxic moieties to the surface of SCLC and perhaps NSCLC cells and perhaps obviate the necessity to internalize the toxin to observe specific cytotoxicity. Further efforts will focus on constructing such molecules in an effort to design antineoplastic therapeutic strategies to disrupt normal membrane signalling processes. The clinical use of membrane-targeted toxins is being developed in ongoing clinical trial with anti-CD22 deglycosylated ricin A chain immunotoxin in B-cell lymphoma, and also an anti CD-19 deglycosylated ricin A chain construction.