De Castiglione R, Gozzini L, Mena R, Brugnolotti M, Ciomei M, Molinari I, Comoglio P M, Gaudino G
Ricerca & Sviluppo Farmitalia Carlo Erba S.r.l., Milano, Italia.
Farmaco. 1990 Dec;45(12):1251-63.
Bombesin is a 14-residue peptide hormone which serves a variety of biological functions, including cell growth control in Swiss 3T3 cultured fibroblasts. It has been also involved in an autocrine system regulating the growth of small cell lung carcinoma. A series of bombesin analogues were developed by amino acid deletion, inversion or substitution in the carboxy-terminal region, identified by the target cell receptor. Their properties were examined for: i) competitive binding assays; ii) mitogenic induction and inhibition assays; iii) effects on early cellular events (inositol phosphates production and protein tyrosine phosphorylation). Inversion of the Trp residue, or deletion of the C-terminal tripeptide amide, induced complete loss of receptor affinity and biological effects. Deletion of the His residue, or its derivatization as His (Dnp) in conjunction with Met deletion or modification, gave rise to compounds with reduced receptor affinity and weak antagonistic properties. Other modifications in the C-terminal tripeptide affected the potency but not the biological profile of the parent peptide. These results indicate the basis for the eventual design of improved, specific bombesin receptor antagonists and stimulate further studies on their possible application in the therapy of human small cell lung cancer.
蛙皮素是一种由14个氨基酸残基组成的肽类激素，具有多种生物学功能，包括调控瑞士3T3培养成纤维细胞的细胞生长。它还参与了调节小细胞肺癌生长的自分泌系统。通过在羧基末端区域进行氨基酸缺失、倒置或取代，开发了一系列蛙皮素类似物，这些类似物由靶细胞受体鉴定。对它们的特性进行了以下检测：i）竞争性结合试验；ii）促有丝分裂诱导和抑制试验；iii）对早期细胞事件（肌醇磷酸生成和蛋白质酪氨酸磷酸化）的影响。色氨酸残基的倒置，或C末端三肽酰胺的缺失，导致受体亲和力和生物学效应完全丧失。组氨酸残基的缺失，或将其衍生化为组氨酸（二硝基苯）并结合甲硫氨酸的缺失或修饰，产生了受体亲和力降低和弱拮抗特性的化合物。C末端三肽的其他修饰影响了母体肽的效力，但不影响其生物学特性。这些结果为最终设计改进的、特异性的蛙皮素受体拮抗剂奠定了基础，并刺激了对其在人类小细胞肺癌治疗中可能应用的进一步研究。
