G-PROTEIN EFFECTORS AS TARGETS FOR ANTINEOPLASTIC THERAPIES

蛙皮素样肽被认为是某些肿瘤的生长因子， 肺癌、乳腺癌和前列腺癌细胞。 已知这些肽 通过鸟嘌呤核苷酸结合的细胞生长调节信号 蛋白质（G蛋白）与磷脂酶等效应物的结合。 由于 由于生长因子受体表达的异质性， 该系统的最佳治疗操作将发生在 受体后水平。 为了破坏G- 蛋白偶联受体如胃泌素释放肽（GRP）和 以马蜂mastoparan为原料，合成了神经介质B（NMB）肽 已知与GT3相互作用并刺激GT3活性的毒液毒素 G蛋白的Gi家族 该系列的结构活性分析 揭示了细胞生长被肽抑制， 电荷间距和两亲性与母体化合物相似。 仅仅 产生具有α-螺旋含量或带正电荷的肽， 不允许发生细胞毒性。 膜破裂的证据， 乳酸脱氢酶的释放和细胞内钙的增加 浓度似乎发生在细胞毒性浓度。 因此，我们认为， 类乳突肽似乎介导肺的生长抑制 肿瘤和Swiss 3 T3细胞通过膜细胞溶解作用，而不是 已知G蛋白偶联效应物的离散调节。 进一步 研究将在亚细胞中确定这些肽是否可以 调节离散的G蛋白偶联效应系统。 的结果 这些研究可能提示用于避免膜溶解的铅结构 影响和调节G蛋白功能。

Bombesin-like peptides have been implicated as growth factors for certain lung, breast, and prostate carcinoma cells. These peptides are known to transduce growth regulatory signals through guanine nucleotide binding proteins(G-proteins) to such effectors as phospholipases. Due to the heterogeneity of growth factor receptor expression, it is possible that the optimal therapeutic manipulation of this system will occur at the post-receptor level. In an effort to disrupt the interaction of G- protein-coupled receptors such as the Gastrin-releasing peptide (GRP) and neuromedia B (NMB) peptides were synthesized based on mastoparan, a wasp venom toxin known to interact with and stimulate the GTPase activity of the Gi family of G-proteins. Structure activity analysis of this series revealed that cell growth was inhibited by peptides which retain a spacing of charge and amphilicity similar to the parent compound. Merely producing peptides with alpha-helical content or with positive charge did not allow cytotoxicity to occur. Evidence of membrane disruption with release of lactate dehydrogenase and increase of intracellular calcium concentration appeared to occur at cytotoxic concentrations. Therefore, mastoparan-like peptides appear to mediate growth inhibition of the lung tumor and Swiss 3T3 cells by a membrane cytolytic effect rather than discrete regulation of known G-protein-coupled effectors. Further studies will define in subcellular factions whether these peptides can regulate discrete G-protein coupled effector systems. The results of these studies may suggest lead structures for avoiding the membrane lytic effect and regulating G-protein function.