BOMBESIN-LIKE PEPTIDE RECEPTORS AND HUMAN LUNG CANCER

蛙皮素样肽（BLP）在人小细胞肺癌中的自分泌生长系统 细胞肺癌（SCLC）作为一种生长因子引起了人们的极大兴趣 可能具有临床应用价值的受体系统。 原本以为 涉及胃泌素释放肽（GRP，哺乳动物铃蟾肽）及其 受体，现在出现的证据表明，一个或多个 相关受体，包括以前未表征的BLP受体， 有助于人类SCLC的恶性生长。 假设是 BLP受体在人SCLC、肺小细胞肺癌、肺巨噬细胞中过表达。 在某些吸烟者中。 这种过度表达有助于 恶性或癌前细胞的增殖优势，并且可以 通过诊断、预后和/或 治疗策略 该提案的总体目标是利用 BLP受体的临床前研究，以进一步开发和应用工具， 确定BLP受体是否可用于改善 肺癌患者。 提供的独特合作机会 这将加速这一努力的成功。 具体目标 本项目的主要内容是：1）确定各种BLP的分布 原位检测正常人肺和人肺癌中的受体 杂交以鉴定表达受体mRNA的细胞， 用高度特异性抗体进行免疫细胞化学以鉴定细胞 表达受体蛋白; 2）评估人类中是否存在变化 肺BLP受体表达：a）发生在吸烟者中， 非吸烟者，B）在肺发育不良发生之前或伴随肺发育不良发生，c） 预测SCLC患者结果，和d）在戒烟后发生和/或 化学预防; 3）鉴定和克隆新的BLP受体， 使用来自非常小细胞肺癌的简并寡核苷酸引物 GRP和神经介肽B受体中的同源序列和PCR， 被用来克隆七膜家族的其他新成员， 跨越结构域受体; 4）BLP受体的效用研究 作为SCLC肿瘤成像和/或使用人 裸鼠中的肿瘤异种移植物。

The autocrine growth system for bombesin-like peptides (BLP) in human small cell lung carcinoma (SCLC) has generated much interest as one growth factor receptor system which may have clinical utility. Originally thought to involve gastrin releasing peptide (GRP, mammalian bombesin) and its receptor, evidence is now emerging that abnormal expression of one or more related receptors, including a previously uncharacterized BLP receptor, contributes to the malignant growth of human SCLC. The hypothesis to be tested is that BLP receptors are overexpressed in human SCLC, pulmonary dysplasia and in some smokers. This overexpression contributes to the proliferative advantage of malignant or premalignant cells and can be exploited to improve patient management via diagnostic, prognostic and/or therapeutic maneuvers. The overall goal of this proposal is to exploit preclinical studies of BLP receptors to further develop and apply tools to determine whether BLP receptors can be utilized to improve management of patients with lung cancer. The unique collaborative opportunities provided by the SPORE will expedite the success of this endeavor. The specific aims of this project are: 1) Determination of the distribution of various BLP receptors in normal human lung and human lung cancer using in situ hybridization to identify cells expressing receptor mRNA and immunocytochemistry with highly specific antibodies to identify cells expressing receptor proteins; 2) Assessment of whether changes in human pulmonary BLP receptor expression: a) occur in smokers compared with nonsmokers, b) precede or accompany development of pulmonary dysplasia, c) predict SCLC patient outcome, and d) occur after smoking cessation and/or chemoprevention; 3) Identification and cloning of novel BLP receptors in human SCLC using degenerate oligonucleotide primers derived from very homologous sequences in the GRP and neuromedin b receptors and PCR as has been used to clone other new members of the family of seven membrane- spanning domain receptors; 4) Investigation of the utility of BLP receptors as potential targets for SCLC tumor imaging and/or treatment using human tumor xenografts in nude mice.