BOMBESIN-LIKE PEPTIDE RECEPTORS AND HUMAN LUNG CANCER

蛙皮素样肽(BLP)在小鼠体内的自分泌生长系统 细胞肺癌(SCLC)作为一种生长因子已引起人们的广泛关注。 可能具有临床实用价值的受体系统。原本以为是 涉及胃泌素释放肽(GRP，哺乳动物蛙皮素)及其 受体，现在有证据表明，一个或多个 相关受体，包括以前未确定特征的BLP受体， 与人小细胞肺癌的恶性生长有关。假设是 BLP受体在人小细胞肺癌、肺小细胞癌中的过度表达 发育不良和一些吸烟者。这种过度表达导致了 恶性或癌前病变细胞的增殖优势 通过诊断、预测和/或改进患者管理 治疗手法。这项提议的总体目标是利用 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对 肺癌患者。提供独特的协作机会 孢子将加速这一努力的成功。具体目标 本项目的主要内容有：1)确定各类BLP的分布 用原位杂交技术检测正常人和肺癌组织中的受体 用杂交法鉴定表达受体mRNA和受体的细胞 免疫细胞化学：用高度特异的抗体识别细胞 表达受体蛋白；2)评估人类 肺BLP受体的表达：A)与吸烟者相比 非吸烟者，b)先于或伴发肺发育不良，c) 预测小细胞肺癌患者的预后，以及d)戒烟和/或 3)新的BLP受体的鉴定和克隆 人小细胞肺癌使用从VERY衍生的简并寡核苷酸引物 GRP和神经介素b受体与聚合酶链式反应的同源序列 被用来克隆七膜家族的其他新成员- 跨域受体；4)BLP受体的用途研究 作为小细胞肺癌肿瘤成像和/或治疗的潜在靶点 裸鼠移植瘤。

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.