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 SCLC细胞的生长，其携带CT的受体，神经节苷脂 G（M1）。 最近，我们完成了一项关于CT对 在非小细胞肺癌（NSCLC）细胞上的一系列生长。 在 与CT介导的G（M1）（+）SCLC细胞生长抑制相反，CT 约50%的NSCLC细胞系可与NSCLC细胞结合， 增加cAMP，但不降低细胞生长。 这些结果提高了 一部分NSCLC细胞系对化疗耐药的可能性 cAMP增加的后果。 在SCLC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）、 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， 肽起起始信号转导的作用。 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G1，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链可用于向细胞递送新的毒性部分 表面上，也许是隐藏的必要性，内化毒素， 观察特异性细胞毒性。 进一步的努力将侧重于 构建这样的分子， 治疗策略来破坏正常的膜信号传导过程。 膜靶向毒素的临床应用正在开发中， 正在进行的抗CD 22去糖基化A链免疫毒素临床试验 IL-2-白喉毒素A链融合蛋白， 皮肤T细胞淋巴瘤

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 G(M1). 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 G(M1)(+) 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 of 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 G1, 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 cell surface 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 trials with anti-CD22 deglycosylated A chain immunotoxin in B-cell lymphoma, and an IL2-diphtheria toxin A chain fusion protein in cutaneous T-cell lymphoma.