Weckbecker G, Raulf F, Stolz B, Bruns C
Preclinical Research, Sandoz Pharma Ltd, Basle, Switzerland.
Pharmacol Ther. 1993 Nov;60(2):245-64. doi: 10.1016/0163-7258(93)90009-3.
Somatostatin (SRIF) is a cyclic tetradecapeptide hormone initially isolated from ovine hypothalami. It inhibits endocrine and exocrine secretion, as well as tumor cell growth, by binding to specific cell surface receptors. Its potent inhibitory activity, however, is limited by its rapid enzymatic degradation and the consequent short plasma half-life. Octreotide is a short SRIF analog with increased duration of action compared to SRIF. Octreotide is approved for the treatment of acromegaly, amine precursor uptake and decarboxylation-omas, complications of pancreatic surgery and severe forms of diarrhea. Preclinical studies have focussed on the anticancer effects of octreotide and the related SRIF analogs BIM 23014 and RC-160. In vitro at nanomolar concentrations, these analogs inhibit the growth of tumor cells that express high affinity SRIF receptors. Accordingly, SRIF analogs, such as octreotide, potently inhibit the growth of SRIF receptor-positive tumors in various rodent models, and, in particular, xenotransplanted human tumors in nude mice. The range of cancers susceptible to octreotide and related SRIF analogs includes mammary, pancreatic, colorectal and lung malignancies. Moreover, an indirect antiproliferative effect of SRIF analogs is achievable in SRIF receptor-negative tumors, whose growth is driven by factors (gastrin, insulin-like growth factor-1, etc.) that are downregulated by SRIF. The use of radiolabeled somatostatin analogs represents a new diagnostic approach. [111In-DTPA]octreotide was developed for gamma camera imaging of SRIF receptor-positive malignancies, such as gasteroenteropancreatic tumors. Visualization of SRIF receptor-positive tumors in humans is emerging as an important methodology, both in tumor staging and predicting therapeutic response to octreotide. Recently, five SRIF receptor subtypes (SSTR1-5) have been cloned, all of which bind SRIF with high affinity. In contrast, SRIF receptor subtypes 1-5 have different binding profiles for short SRIF analogs. Octreotide, SSTR5, show moderate affinity for SSTR3 and fail to bind with high affinity to the other subtypes (SSTR1 and 4). Accordingly, the oncological profile of these three analogs is apparently similar. In conclusion, somatostatin analogs are a promising class of compounds for diagnosis and treatment of cancer. Current work is focussed on the identification of further SRIF receptor subtype-selective analogs with potential in oncology.
生长抑素（SRIF）是一种环状十四肽激素，最初从羊下丘脑分离得到。它通过与特定细胞表面受体结合来抑制内分泌和外分泌分泌，以及肿瘤细胞生长。然而，其强大的抑制活性受到其快速酶解以及随之而来的短血浆半衰期的限制。奥曲肽是一种短效SRIF类似物，与SRIF相比作用持续时间延长。奥曲肽被批准用于治疗肢端肥大症、胺前体摄取和脱羧瘤、胰腺手术并发症以及严重腹泻。临床前研究集中在奥曲肽以及相关SRIF类似物BIM 23014和RC - 160的抗癌作用上。在体外，这些类似物在纳摩尔浓度下可抑制表达高亲和力SRIF受体的肿瘤细胞生长。因此，SRIF类似物，如奥曲肽，在各种啮齿动物模型中能有效抑制SRIF受体阳性肿瘤的生长，尤其是裸鼠体内的人异种移植肿瘤。对奥曲肽和相关SRIF类似物敏感的癌症范围包括乳腺癌、胰腺癌、结直肠癌和肺癌。此外，SRIF类似物在SRIF受体阴性肿瘤中可产生间接抗增殖作用，这些肿瘤的生长由SRIF下调的因子（胃泌素、胰岛素样生长因子 - 1等）驱动。使用放射性标记的生长抑素类似物代表了一种新的诊断方法。[111In - DTPA]奥曲肽被开发用于对SRIF受体阳性恶性肿瘤，如胃肠胰腺肿瘤进行γ相机成像。在人类中，SRIF受体阳性肿瘤的可视化正成为一种重要方法，在肿瘤分期和预测对奥曲肽的治疗反应方面都有应用。最近，已克隆出五种SRIF受体亚型（SSTR1 - 5），它们都能与SRIF高亲和力结合。相比之下，SRIF受体亚型1 - 5对短效SRIF类似物有不同的结合特征。奥曲肽对SSTR5、SSTR3显示中等亲和力，对其他亚型（SSTR1和4）则不能高亲和力结合。因此，这三种类似物的肿瘤学特征显然相似。总之，生长抑素类似物是一类有前途的用于癌症诊断和治疗的化合物。目前的工作集中在鉴定具有肿瘤学潜力的进一步的SRIF受体亚型选择性类似物。
