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。 为了更精确地定义 蛙皮素样肽neuromedin-b（NMB）的作用， 其中大鼠NMB受体（NMB-R）基因被引入到 Balb 3 T3细胞不表达铃蟾肽受体。 的 所得细胞系NMB-8表达800，000个NMB结合位点/细胞。 添加NMB对[3 H]胸苷（[3 H] dT）具有双相效应 融合和静止细胞中的掺入：高达10 nM的NMB导致 1.5-3倍刺激（3 H]dT掺入，但大于10 NM中，[3 H] dT掺入响应于 在100 nM的NMB下，细胞生长受到抑制。 NMB 导致细胞内Ca 2+的持续增加，以及百日咳 毒素（PT）不敏感，但鸟苷5 '-o-[3-硫代三磷酸]- 刺激磷脂酶-C活性增加。花生四烯酸的释放是 也以PT不敏感的方式被NMB激活。 短期暴露于 12-十四酰基-佛波醇-13-乙酸酯抑制NMB介导的 磷脂酰肌醇周转而不是花生四烯酸释放。 我们的结论 NMB-R可促进[3 H]dT参入，但持续性 大量受体的激活可能会抑制细胞生长 与第二信使分子的不受控制的加工有关。 进一步的研究表明，以第三种蛋白质为模型的肽 神经介肽和蛙皮素受体的胞浆内环， 马蜂毒素mastoparan具有肺生长抑制特性 肿瘤细胞系 这些肽的作用机制 通过调节G蛋白作用或通过 细胞膜的改变目前正在研究中。

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. To define more precisely the effectors of the bombesin-like peptide neuromedin-b(NMB)'s action, transfectants were created in which the rat NMB receptor (NMB-R)gene was introduced into Balb 3T3 cells which do not express bombesin peptide receptors. The resultant cell line, NMB-8, expresses 800,000 NMB binding sites/cell. Addition of NMB has a biphasic effect on [3H]thymidine([3H)dT) incorporation in confluent and quiescent cells: up to 10 nM of NMB causes a 1.5-3 fold stimulation of (3H]dT incorporation, but at greater than 10 NM there is clear inhibition of [3H)dT incorporation in response to ligand, and at 100 nM of NMB there was inhibition of cell growth. NMB causes protracted increases in intracellular Ca2+, as well as pertussis toxin(PT) - insensitive but guanosine5'-o-[3-thiotriphosphate]- stimulated increase in phospholipase-C activity. Arachidonate release was also activated by NMB in a PT-insensitive manner. Short term exposure to 12-tetradecanoyl-phorbol-13-acetate inhibited NMB-mediated phosphatidylinositol turnover but not arachidonate release. We conclude that NMB-R can promote [3H]dT incorporation, but that persistent activation of large numbers of receptors may inhibit cell growth perhaps related to the unregulated elaboration of second-messenger molecules. Additional studies have revealed that peptides modeled on the third intracytoplasmic loop of the neuromedin and bombesin receptors and on the wasp venom toxin mastoparan possess growth inhibitory properties for lung tumor cell lines. Whether the mechanism for these peptides' action proceeds through a modulation of G-protein action or through an alteration of the cell membrane in currently under study.