权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Development of various somatostatin analogs for the treatment and diagnosis of tumors utilizing somatostatin receptor genes

利用生长抑素受体基因开发用于治疗和诊断肿瘤的各种生长抑素类似物

基本信息

批准号：
04557131
负责人：
SEINO Susumu
金额：
$ 7.49万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-04557131/
关键词：
Somatostatin Receptors G-protein Tumors Somatostatin Analogs Receptor-imaging

项目摘要

Somatostatin exerts its effect through its specific high affinity receptors. We have previously reported cloning, functional characterization, and tissue distribution of two subtypes of human and mouse somatostatin receptors (SSTR1, SSTR2). In the present study, we have cloned three additional human somatostatin receptors (SSTR1, SSTR2, SSTR3). Human SSTR1, SSTR2, and SSTR3 are proteins of 418, 388, and 364 amino acids, respectively, RNA blotting studies have revealed that SSTR3 mRNA was detected in human brain and SSTR4 mRNA was present in human pancreatic cancer cell line, MIA PaCa2, while SSTR5 mRNA was not detected in the human tissues examined. The SSTR3 mRNA was expressed at high levels in rat pancreatic islets as well. The human SSTR3, SSTR4, and SSTR5 exhibit specfic binding to somatostatin-14 with IC50 values 1.7, 1.6 and 0.16nM, respectively. We also have characterized the binding affinity of various somatostatin analogs to the SSTR3, 4, and 5. The rank of the potency of the analogs are : somatostatin 28 (SS-28) = CGP 23996>somatostatin-14 (SS-14)>SMS201-995 for hSSTR3 ; SS-14=SS-28>>RC-160>>SMS201-995 for hSSTR4 and SS-28>SS-14>>RC-160>SMS201-995 for hSSTR5. We have determined somatostatin receptor subtypes expressed human endocrine tumors. In two cases of glucagonomas, all the SSTR subtype mRNAs except for SSTR5 mRNA were expressed. In 4 cases of insulinoma, there was a heterogeneous expression hSSTRs. In a carcinoid, SSTR1 and SSTR4 mRNA were detected. Since somatostatin analog, SMS201-995 which has been approved for the treatment of endocrine tumors, was effective in the treatment of a patient with glucagonoma in which SSTR2 mRNA was present, whereas it had no effect in a patient with carcinoid in which SSTR2 mRNA was not detected, these results suggest that the efficacy of SMS201-995 may depend, at least in part, on the expression of SSTR2 in tumors. Cloning of five human somatostatin receptor subtypes facilitates the development of various somatosta

生长抑素通过其特异性高亲和力受体发挥作用。我们之前报道了人类和小鼠生长抑素受体（SSTR1, SSTR2）的两种亚型的克隆、功能表征和组织分布。在本研究中，我们克隆了另外三个人类生长抑素受体（SSTR1, SSTR2, SSTR3）。人SSTR1、SSTR2和SSTR3分别是418、388和364个氨基酸的蛋白，RNA印迹研究显示，在人脑中检测到SSTR3 mRNA，在人胰腺癌细胞系MIA PaCa2中检测到SSTR4 mRNA，而在所检查的人体组织中未检测到SSTR5 mRNA。SSTR3 mRNA在大鼠胰岛中也有高水平表达。人SSTR3、SSTR4和SSTR5与生长抑素-14特异性结合，IC50值分别为1.7、1.6和0.16nM。我们还描述了各种生长抑素类似物与SSTR3、4和5的结合亲和力。类似物效价排序为：生长抑素28 (SS-28) = CGP 23996>；生长抑素14 (SS-14)>SMS201-995；SS-14=SS-28>>RC-160>>SMS201-995适用于hSSTR4和SS-28>SS-14>>RC-160>SMS201-995适用于hSSTR5。我们已经确定了表达人内分泌肿瘤的生长抑素受体亚型。在两例胰高血糖素升高中，除SSTR5 mRNA外，所有SSTR亚型mRNA均表达。4例胰岛素瘤中存在异质表达hSSTRs。在类癌中，检测到SSTR1和SSTR4 mRNA。由于生长抑素类似物SMS201-995已被批准用于治疗内分泌肿瘤，对存在SSTR2 mRNA的胰高血糖素患者有效，而对未检测到SSTR2 mRNA的类癌患者无效，这些结果表明SMS201-995的疗效可能至少部分取决于肿瘤中SSTR2的表达。克隆五种人类生长抑素受体亚型促进了各种生长障碍的发展