Reubi Jean Claude, Eisenwiener Klaus-Peter, Rink Hans, Waser Beatrice, Mäcke Helmut R
Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Switzerland.
Eur J Pharmacol. 2002 Dec 5;456(1-3):45-9. doi: 10.1016/s0014-2999(02)02651-1.
All commercially available somatostatin analogs for clinical use have a preference for some but not all somatostatin receptor subtypes. We describe here the synthesis and evaluation in binding and cAMP assays with cell lines stably transfected with sst(1)-sst(5) of a new type of nonapeptide somatostatin analog with a reduced-sized and stabilized structure, Tyr(0)-(cyclo-D-Dab-Arg-Phe-Phe-D-Trp-Lys-Thr-Phe) (KE108). All five somatostatin receptors subtypes have an extremely high affinity for KE108, equivalent to SS-28 at sst(1) and two to four times higher than SS-28 at sst(2), sst(3), sst(4) and sst(5). Moreover, the compound has agonistic properties at all five subtypes, since it is able to inhibit the forskolin-stimulated cAMP production in sst(1)-sst(5) cells. It is stable for several hours in human serum. This analog may therefore represent a considerable improvement over commercially available somatostatin analogs as it will target all somatostatin receptor subtypes, a particular advantage for cancer-related applications, as human cancers can express concomitantly several somatostatin receptor subtypes.
所有市售的用于临床的生长抑素类似物对某些但并非所有生长抑素受体亚型都有偏好。我们在此描述一种新型九肽生长抑素类似物Tyr(0)-(环-D- Dab-Arg-Phe-Phe-D-Trp-Lys-Thr-Phe)(KE108)的合成，并通过与稳定转染了sst(1)-sst(5)的细胞系进行结合和cAMP分析来评估。所有五种生长抑素受体亚型对KE108都具有极高的亲和力，在sst(1)上与SS-28相当，在sst(2)、sst(3)、sst(4)和sst(5)上比SS-28高两到四倍。此外，该化合物在所有五种亚型上都具有激动特性，因为它能够抑制sst(1)-sst(5)细胞中福斯高林刺激的cAMP产生。它在人血清中能稳定存在数小时。因此，这种类似物可能比市售的生长抑素类似物有显著改进，因为它能靶向所有生长抑素受体亚型，这对于癌症相关应用是一个特别的优势，因为人类癌症可同时表达多种生长抑素受体亚型。
