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诱导 包括细胞内钙离子([Ca2+]i)升高和 人小细胞肺癌中磷脂酰肌醇的转化 细胞。这种影响伴随着循环频率的增加而发生。 毒素诱导的AMP(CAMP)。此外，这种毒素还能抑制 携带CT受体的SCLC细胞的生长，神经节苷脂GM1。 最近，我们完成了CT对生长的影响的分析 关于非小细胞肺癌(NSCLC)细胞的一系列研究。相比之下， CT对GM1(+)小细胞肺癌细胞生长的抑制作用 约50%的非小细胞肺癌细胞能与非小细胞肺癌细胞结合，增加 CAMP，但不会减少细胞生长。这些结果增加了一种可能性 一小部分非小细胞肺癌细胞系对后果是不耐受的 增加营地的数量。在小细胞肺癌中，最近的实验表明 CT作用的结果是抑制膜脂合成 包括磷脂酰肌醇、磷脂酰肌醇-4‘-磷酸(PIP)、L 和磷脂酰肌醇-4，5-二磷酸(PIP)2。这些结果将 提示CT作用于破坏轰炸素作用的正常底物 多肽的作用是启动信号转导。这些结果进一步 建议选择性地传递CT A链，它激活腺苷 通过Gs的共价修饰环化酶，将是一种有用的手段 靶向蛙皮素肽介导的信号转导。此外, CT-B链可用于将新的有毒部分输送到 小细胞肺癌和非小细胞肺癌细胞的表面，也许消除了 将毒素内化，观察其特异性细胞毒性。进一步 努力将重点放在构建这种分子上，以努力设计 破坏正常膜的抗肿瘤治疗策略 信令过程。膜靶向毒素的临床应用是 正在进行的临床试验中正在开发抗CD22脱糖基抗体 B细胞淋巴瘤中的蓖麻毒素A链免疫毒素和抗CD-19 脱糖蓖麻毒素A链结构。

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.