Reubi J C, Kvols L K, Waser B, Nagorney D M, Heitz P U, Charboneau J W, Reading C C, Moertel C
Sandoz Research Institute Berne, Berne, Switzerland.
Cancer Res. 1990 Sep 15;50(18):5969-77.
Somatostatin (SS) receptor status was investigated in the tumor tissues from 62 patients with carcinoid tumors and 15 patients with islet cell carcinomas using receptor autoradiography techniques with two different iodinated somatostatin analogues as radioligands, a [Leu8, DTrp22, Tyr25]somatostatin-28 and a somatostatin octapeptide, Tyr3-octreotide. The carcinoid tumors were either primaries (n = 32) or metastases (n = 43), sampled as surgical specimens or as small needle liver biopsies. Fifty-four of 62 carcinoid patients had SS receptor-positive tumors (87%). All 15 islet cell carcinoma patients had positive tumors (4 primaries, 11 metastases), i.e., 3 vipomas, 3 insulinomas, 2 glucagonomas, 1 gastrinoma, 2 polyfunctional tumors, and 4 nonfunctioning tumors. Saturation and competition experiments on tissue sections revealed saturable, high affinity binding sites pharmacologically specific for bioactive SS analogues. In a majority of the tumors, the receptors were densely distributed and were always homogeneously found in the whole tumor. All except two tumors were labeled with both radioligands. Multiple liver metastases (n = 16) from three different patients were all shown to contain a comparable amount of receptors. SS receptors could be demonstrated even in very small tissue samples of liver metastases obtained by percutaneous liver biopsies (mean weight, 6.8 mg). The majority of the eight SS receptor-negative carcinoids were mainly bronchial carcinoids (n = 5), usually poorly differentiated. On the contrary, SS receptor-positive cases were never found to be anaplastic. All tumors except one from patients pretreated with octreotide (3 days to 3.8 years) were SS receptor positive. In the majority of carcinoids or islet cell carcinomas, the SS receptor status correlated with the in vivo biochemical response (hormone inhibition) to octreotide. These data demonstrate (a) the high prevalence of SS receptors in the primary tumors of both carcinoids and islet cell carcinomas, (b) their presence in metastases as well, (c) their continuous expression even during long term octreotide therapy, (d) the possibility of measuring SS receptors in percutaneous needle liver biopsies, and (e) the evidence of their functionality. This study therefore suggests that tumoral SS receptors may be the likely molecular basis for octreotide action and may be an important parameter for predicting the therapeutic efficacy of SS analogues in carcinoids and islet cell carcinomas.
采用受体放射自显影技术,以两种不同的碘化生长抑素类似物作为放射性配体,一个是[亮氨酸8、多巴22、酪氨酸25]生长抑素-28,另一个是生长抑素八肽,替曲肽,对62例类癌患者和15例胰岛细胞瘤患者的肿瘤组织进行生长抑素(SS)受体状态研究。类癌组织样本为手术标本或经皮肝穿刺活检的小块肝组织,其中原发性肿瘤32例,转移瘤43例。62例类癌患者中有54例肿瘤组织生长抑素受体呈阳性(87%)。15例胰岛细胞瘤患者的肿瘤组织均呈阳性(4例原发性肿瘤,11例转移瘤),即3例血管活性肠肽瘤、3例胰岛素瘤、2例胰高血糖素瘤、1例胃泌素瘤、2例多功能肿瘤和4例无功能性肿瘤。组织切片的饱和与竞争实验显示,这些结合位点具有可饱和性、高亲和力,且对生物活性生长抑素类似物具有药理学特异性。在大多数肿瘤中,受体分布密集,且在整个肿瘤中均匀分布。除2例肿瘤外,其余肿瘤均被两种放射性配体标记。来自3例不同患者的16个肝转移瘤均显示含有相当数量的受体。即使是经皮肝穿刺活检获得的非常小的肝转移瘤组织样本(平均重量6.8mg)也能检测到生长抑素受体。8例生长抑素受体阴性的类癌主要为支气管类癌(5例),通常分化较差。相反,从未发现生长抑素受体阳性的病例为间变。除1例接受过奥曲肽治疗(3天至3.8年)的患者外,所有肿瘤生长抑素受体均为阳性。在大多数类癌或胰岛细胞瘤中,生长抑素受体状态与对奥曲肽的体内生化反应(激素抑制)相关。这些数据表明:(a)生长抑素受体在类癌和胰岛细胞瘤的原发性肿瘤中普遍存在;(b)在转移瘤中也存在;(c)即使在长期奥曲肽治疗期间仍持续表达;(d)经皮肝穿刺活检可检测生长抑素受体;(e)有证据表明其具有功能。因此,本研究提示肿瘤生长抑素受体可能是奥曲肽作用的分子基础,可能是预测生长抑素类似物对类癌和胰岛细胞瘤治疗疗效的重要参数。