In vitro binding evaluation of 177Lu-AMBA, a novel 177Lu-labeled GRP-R agonist for systemic radiotherapy in human tissues
In vitro binding evaluation of 177Lu-AMBA, a novel 177Lu-labeled GRP-R agonist for systemic radiotherapy in human tissues
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DOI：
10.1007/s10585-008-9220-0
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发表时间：
2009-02-01
影响因子：
4
通讯作者：
Nunn, Adrian D.
中科院分区：
文献类型：
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作者：
Thomas, Regi;Chen, Jianqing;Nunn, Adrian D.
胃泌素释放肽（GRP）家族成员及其类似物bombesin （BBN）与多种人类癌症（包括前列腺癌、乳腺癌、结肠癌和肺癌）的生物学有关。迄今为止，已经克隆并鉴定了三种哺乳动物GRP/BBN受体亚型：神经素B受体（NMBR）、GRP受体（GRPR）和BBN受体亚型3 （BB3）。第四种BBN受体亚型BB4仅在两栖动物中被发现，目前尚未发现与该受体相当的哺乳动物。GRPR类似物已被用作运载药物、放射性核素和细胞毒素的载体，以靶向各种GRPR阳性的癌症类型。我们研究了lu177 - amba的体外结合特性，lu177 - amba是一种新型放射性标记BBN类似物，目前正在临床试验中作为激素难治性前列腺癌（HRPC）患者的全身放疗。采用含有特定受体亚型的膜靶系统进行体外结合研究，确定了Lu-177-AMBA的药理学分析。我们通过受体放射自显影研究了lu177 - amba在人肿瘤和非肿瘤组织中的结合位点分布。药理特性表明，Lu-177-AMBA对NMB和GRP受体具有较高的亲和力，而对BB3受体亲和力较低或无亲和力。在40种不同类型的非肿瘤组织中，其中7种显示出有限但特异性的Lu-177-AMBA结合。17例原发性前列腺癌中的14例，13例原发性乳腺癌中的6例表达了Lu-177-AMBA的结合位点。此外，在配对对（原发性和继发性）前列腺癌和乳腺癌组织中，lu177 - amba结合位点的表达没有明显差异。这些数据为Lu-177-AMBA临床应用于GRP-R和NMB-R阳性肿瘤的诊断和治疗提供了分子基础。
Members of the gastrin-releasing peptide (GRP) family and its analogs bombesin (BBN) have been implicated in the biology of several human cancers including prostate, breast, colon and lung. To date, three mammalian GRP/BBN receptor subtypes have been cloned and characterized: the neuromedin B receptor (NMBR), the GRP receptor (GRPR) and the BBN-receptor subtype 3 (BB3). The fourth BBN receptor subtype, BB4, has only been identified in amphibian and at present no mammalian equivalent of this receptor has been described. GRPR analogs have been used as carriers to deliver drugs, radionuclides and cytotoxins to target various cancer types that are GRPR positive. We investigated the in vitro binding properties of Lu-177-AMBA, a novel radiolabelled BBN analog currently undergoing clinical trial as systemic radiotherapy for hormone refractory prostate cancer (HRPC) patients. Pharmacological analyses of the Lu-177-AMBA was determined using in vitro binding studies using membrane target system containing specific receptor subtypes. We investigated the distribution of binding sites for Lu-177-AMBA by receptor autoradiography on human neoplastic and non-neoplastic tissues. Pharmacological characterizations of Lu-177-AMBA shows, high affinity towards NMB and GRP receptors, while little or no affinity towards BB3 receptor. Among the 40 different types of non-neoplastic tissues tested seven of them showed limited but specific binding of Lu-177-AMBA. Fourteen of 17 primary prostate cancers, six of 13 primary breast cancers expressed binding sites for Lu-177-AMBA. Furthermore, no apparent differences in Lu-177-AMBA-binding sites expression were observed between matched pairs (primary vs. secondary) of prostate and breast cancer tissues. These data represent the molecular basis for clinical applications of Lu-177-AMBA for diagnosis and treatment of GRP-R and NMB-R positive tumors.