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神经内分泌肿瘤(neuroendocrine neoplasm,NEN)是起源于神经内分泌细胞的一种异质性肿瘤,几乎可以发生在任何器官,但以胰腺、胃肠道和肺最为常见(约占95%以上)[1-3]。1/3的NEN为功能性肿瘤,可引起腹泻、潮红、出汗和支气管痉挛等非典型临床症状,经常被误诊为更年期、肠易激综合征、焦虑状态、过敏或哮喘等;而非功能性NEN并无特殊的临床症状,因此,NEN较难被早期诊断,通常在疾病晚期才确诊,确诊时间平均延迟3~10年[4]。40%~95%的胃肠胰NEN患者在确诊时已发生转移[5]。近40年来,NEN的发病率逐年升高[6]。提高NEN的早期诊断率、对NEN进行准确分期以及选择合适的治疗方法对于改善NEN患者的预后十分重要。
80%~90%的NEN高表达生长抑素受体(somatostatin receptor,SSTR),特别是SSTR2,其是NEN分子显像和核素靶向治疗的靶点。通过螯合剂的介导,放射性核素可与生长抑素类似物(somatostatin analogue,SSA)结合形成稳定的复合物,该复合物与SSTR结合可实现核素显像和治疗。NEN分子显像在原发肿瘤的诊断、临床分期、术前分级和疗效评估等方面发挥着重要作用,从而使NEN的早期诊断成为可能[7-8]。更重要的是,其能评估患者是否能从核素标记SSTR的肽受体放射性核素治疗(peptide receptor radionuclide therapy,PRRT)和非核素标记的SSA药物治疗中获益。核素标记SSTR的PRRT可为失去手术机会或多线治疗失败的SSTR阳性的NEN患者带来希望,改善其生活质量并延长其无进展生存期,核素标记SSTR的PRRT的临床效果优于非核素标记的SSA药物治疗[9]。
SSA药物包括SSTR激动剂和拮抗剂。SSTR激动剂可在配体与受体相互作用后通过受体介导的内吞作用内化到肿瘤细胞内,从而在肿瘤细胞内积聚,而SSTR拮抗剂则不能[10-12]。过去,人们认为核素标记的SSTR激动剂内化到肿瘤细胞内能延长核素的滞留时间,从而增加肿瘤的辐射剂量,显像和治疗效果会更好,据此,研究者致力于开发核素标记的SSTR激动剂,目前获得美国食品药品监督管理局(FDA)批准、临床上广泛用于NEN患者SSTR显像和PRRT的SSA药物均为SSTR激动剂[13-16]。而近年来的体内外研究结果显示,NEN对SSTR拮抗剂的摄取率高于SSTR激动剂,且前者在肿瘤细胞内的滞留时间长于后者[17-20],因此,使用核素标记的SSTR拮抗剂成为NEN分子显像和治疗的一种新方法。我们将综述核素标记的SSTR拮抗剂在NEN显像和治疗中的研究进展,讨论其在NEN诊疗中的优势,为临床诊疗决策提供参考。
核素标记的生长抑素受体拮抗剂在神经内分泌肿瘤显像和治疗中的研究进展
Research progress of radionuclide-labeled somatostatin receptor antagonists in the imaging and treatment of neuroendocrine neoplasms
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摘要: 生长抑素受体(SSTR)特别是SSTR2过表达是神经内分泌肿瘤(NEN)的共同特征,也是NEN分子显像和核素靶向治疗的理想靶点。过去,研究者们一直致力于核素标记的SSTR激动剂的研究,并成功将其应用于NEN的临床显像和治疗。近年来的研究结果表明,核素标记的SSTR拮抗剂比激动剂具有更好的药代动力学特性,其肿瘤摄取率更高、滞留时间更长,且所获得的影像对比度更高,故其在NEN的分子显像和核素靶向治疗中更具优越性。笔者就核素标记的SSTR拮抗剂在NEN显像和治疗中的研究进展进行综述,以期为NEN的临床诊疗提供参考。Abstract: Overexpression of somatostatin receptors (SSTR), especially SSTR2 is a common feature of neuroendocrine neoplasms (NEN) and an ideal target for NEN molecular imaging and radionuclide-targeted therapy. In the past, researchers have been working on radionuclide-labeled SSTR agonists, and have successfully used them for clinical imaging and treatment of NEN. Recent studies have shown that radionuclide-labeled SSTR antagonists have better pharmacokinetic characteristics, higher tumor uptake rates, longer retention time, and higher image contrast obtained than agonists. They are more superior in molecular imaging and radionuclide-targeted therapy of NEN. In this paper, the research progress of radionuclide-labeled SSTR antagonists in the imaging and treatment of NEN is reviewed, in order to provide reference for the clinical diagnosis and treatment of NEN.
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