背景：帕瑞肽是第二代生长抑素（SRIF）受体配体（SRL），批准用于肢端肥大症和库欣病（CD）的医疗治疗。该分子是基于SRIF结构合成的稳定的环己肽。与第一代SRL（例如奥曲肽）不同，优先结合生长抑素受体（SST）亚型2（SST2），帕瑞肽对多个SST具有高亲和力(SST5>SST2>SST3>SST1)。有趣的是,早期临床前研究表明,与SRIF和第一代SRLs结合SST时,帕瑞肽显示出不同的功能特性.
方法：我们旨在强调帕瑞肽在生长激素和促肾上腺皮质激素腺瘤治疗中的不同受体靶向作用，在对肢端肥大症和CD模型进行的临床前研究的整个重要修订过程中。
结果：不同作者证明，帕瑞肽在生长激素腺瘤细胞培养物中的抗分泌作用与SST2-优先激动剂奥曲肽相当。一些报道甚至显示了Pasireotide治疗后SST2mRNA表达与GH减少之间的直接相关性，从而奠定了SST2在体外促生长素瘤中驱动帕瑞肽功效的主要作用。另一方面,帕瑞肽对促肾上腺皮质激素瘤细胞分泌ACTH的抑制作用似乎主要由SST5介导。的确,与SST2优先激动剂相比，大多数报告显示帕瑞肽的效力和功效更高，而功能研究证实了SST5靶向在促肾上腺皮质激素细胞中的关键作用。
结论：在生长激素和皮质腺瘤中进行的临床前研究的分析指出，帕西瑞肽显示出细胞特异性活性，在不同的腺瘤组织型中通过不同的SST发挥其生物学效应。
BACKGROUND: Pasireotide is a second-generation somatostatin (SRIF) receptor ligand (SRL), approved for medical treatment of acromegaly and Cushing\'s disease (CD). The molecule is a stable cyclohexapeptide synthetized based on SRIF structure. Differently from first-generation SRLs (e.g. octreotide), preferentially binding somatostatin receptor (SST) subtype 2 (SST2), pasireotide has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). Interestingly, early preclinical studies demonstrated that pasireotide shows distinct functional properties compared to SRIF and first-generation SRLs when binding SSTs.
METHODS: We aimed to highlight the differential receptor-targeted action of pasireotide in the treatment of somatotroph and corticotroph adenomas, throughout the critical revision of preclinical studies carried out on acromegaly and CD models.
RESULTS: Different authors demonstrated that the antisecretory effect of pasireotide in somatotroph adenoma cell cultures is comparable to that of the SST2-preferential agonist octreotide. Some reports even show a direct correlation between SST2 mRNA expression and GH reduction after pasireotide treatment, thus laying for a predominant role of SST2 in driving pasireotide efficacy in somatotropinomas in vitro. On the other hand, the inhibitory effect of pasireotide on ACTH secretion in corticotropinoma cells seems to be mainly mediated by SST5. Indeed, most reports show a higher potency and efficacy of pasireotide compared to SST2 preferential agonists, while functional studies confirm the pivotal role of SST5 targeting in corticotroph cells.
CONCLUSIONS: The analysis of preclinical studies carried out in somatotroph and corticoph adenomas points out that pasireotide shows a cell-specific activity, exerting its biological effects via different SSTs in the different adenoma histotypes.
PDF(Sci-hub)