The three-dimensional NMR structures of six analogues of somatostatin (SRIF) are described. These analogues with the amino acid 4-(N-isopropyl)-aminomethylphenylalanine (IAmp) at position 9 exhibit potent and highly selective binding to human SRIF subtype 1 receptors (sst1). The conformations reveal that the backbones of these analogues have a hairpin-like structure similar to the sst2-subtype-selective analogues. This structure serves as a scaffold for retaining a unique arrangement of the side chains of d-Trp8, IAmp9, Phe7, and Phe11 or m-I-Tyr11 (m-I-Tyr = mono-iodo-tyrosine). The conformational preferences and results from biological analyses of these analogues1,2 allow a detailed study of the structure−activity relationship of SRIF. The proposed consensus pharmacophore of the sst1-selective analogues requires a unique set of distances between an indole/2-naphthyl ring, an IAmp side chain, and two aromatic rings. This motif is necessary and sufficient to explain the binding affinities of all of the analogues studied and is distinct from the existing models suggested for sst4 as well as sst2/sst5 selectivity.
Bombesin and bombesin receptors have been shown to play a role in cancer. Whereas the gastrin-releasing peptide (GRP) receptor is a bombesin receptor subtype frequently expressed by tumors, the other three subtypes, the neuromedin B (NMB), BB3, and BB4 receptors, have been poorly investigated in human tissues.We investigated 161 human tumors for their bombesin receptor subtype expression using in vitro receptor autoradiography with the universal bombesin radioligand (125)I-[D-Tyr(6), beta-Ala(11), Phe(13), Nle(14)]bombesin(6-14) in displacement experiments with unlabeled GRP, bombesin, NMB, and [D-Tyr(6), beta-Ala(11), Phe(13), Nle(14)]bombesin(6-14). The distinct rank order of potencies of these analogues for each receptor subtype allows us to identify the predominant subtype expressed by each tumor.Twelve of 12 prostate cancers, 41 of 57 breast cancers, and 5 of 5 gastrinomas expressed predominantly GRP receptors; 11 of 24 intestinal, 1 of 26 bronchial, and 1 of 1 thymic carcinoids had preferentially NMB receptors; 9 of 26 bronchial carcinoids, 1 large cell neuroendocrine lung carcinoma, and 4 of 9 small cell lung carcinomas had preferentially BB3 receptors, whereas 3 of 9 small cell lung carcinomas had GRP receptors. Renal cell carcinomas had GRP receptors in 6 of 16 cases and BB3 receptors in 4 of 16 cases. Finally, 2 of 10 Ewing sarcomas had BB3 receptors. In situ hybridization detected BB3 receptor mRNA in neuroendocrine tumors expressing the BB3 protein.This is the first study detecting the proteins of BB3, NMB, and GRP receptors in a group of human tumors using differential binding techniques. Particularly relevant is the BB3 expression in lung carcinoids and other neuroendocrine lung tumors, whereas gastrointestinal carcinoids preferably express NMB receptors. These tumors may be targets for diagnostic and radiotherapeutic applications of subtype-selective bombesin analogues.
While incretins are of great interest for the therapy of diabetes 2, the focus has recently been brought to the thyroid, since rodents treated with glucagon-like peptide-1 (GLP-1) analogs were found to occasionally develop medullary thyroid carcinomas. Incretin receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) were therefore measured in various rodent and human thyroid conditions. In vitroGLP-1 and GIP receptor autoradiography were performed in normal thyroids, C-cell hyperplasia and medullary thyroid carcinomas in rodents. Receptor incidence and density were assessed and compared with the receptor expression in human thyroids, medullary thyroid carcinomas, and TT cells. GLP-1 receptors are expressed in C cells of normal rat and mice thyroids. Their density is markedly increased in rat C-cell hyperplasia and medullary thyroid carcinomas, where their incidence amounts to 100%. GIP receptors are neither detected in normal rodent thyroids nor in C-cell hyperplasia, but are present in all rat medullary thyroid carcinomas. No GLP-1 or GIP receptors are detected in normal human thyroids. Whereas only 27% of all human medullary thyroid carcinomas express GLP-1 receptors, up to 89% express GIP receptors in a high density. TT cells lack GLP-1 receptors but express GIP receptors. GLP-1 receptors are frequently expressed in non-neoplastic and neoplastic C cells in rodents while they are rarely detected in human C-cell neoplasia, suggesting species differences. Conversely, GIP receptors appear to be massively overexpressed in neoplastic C cells in both species. The presence of incretin receptors in thyroid C cell lesions suggests that this organ should be monitored before and during incretin-based therapy of diabetes.
The prognostic significance, as well as the relationship with known prognostic factors in breast cancer, of insulin-like growth factor 1 receptor (IGF-1-R), epidermal growth factor receptor (EGF-R), and somatostatin receptor (SS-R) was evaluated. IGF-1-R was positively correlated with estrogen receptor and age, but not significantly with progesterone receptor, lymph node status, and tumor size. EGF-R was negatively correlated to estrogen receptor and progesterone receptor, whereas no association was found with age, lymph node status, and tumor size. The levels of the tumor contents of IGF-1-R and EGF-R were not significantly related to tumor recurrence in 214 patients (test for trend, P = 0.20 and P = 0.08, respectively). However, patients with tumors containing intermediate levels of EGF-R (0.5 to 2.0 fmol/mg of membrane protein) experienced a longer disease-free survival than did patients with tumors possessing lower or higher levels of EGF-R. This effect was most pronounced in the subgroup of patients with positive axillary lymph nodes: 66% disease-free after 5 yr compared with 38% and 46% for the groups with lower and higher EGF-R levels, respectively. The relapse-free survival for patients with tumors containing SS-R (15%) was significantly longer than for patients with SS-R-negative tumors (82% versus 46% disease free after 5 yr, P = 0.04). Assessment by multivariate analysis showed that lymph node status, tumor size, and differentiation grade were independent prognostic factors for relapse. In the Cox model, estrogen receptor and progesterone receptor were both negatively correlated with tumor recurrence, whereas overall EGF-R and IGF-1-R did not show such a relation.
Severe cases of postprandial hypoglycaemia after bariatric surgery can be a diagnostic and therapeutic challenge. The diagnostic role of 68Ga-DOTA-Exendin-4 PET/CT in postbariatric hypoglycaemia for further treatment decisions is unclear. We present a case of a 50-year-old woman with frequent and severe postprandial hypoglycaemic (≤2.5 mmol/L) episodes starting three years after Roux-Y gastric bypass. Despite strict dietary adherence and several medical therapies, the patient remained severely affected, and 68Ga-DOTA-Exendin-4 PET/CT was performed to exclude atypical presentation of an insulinoma or nesidioblastosis. No pancreatic abnormalities were found, but intensive tracer accumulation in the first and second part of the duodenum was detected, which proved to be hyperplastic Brunner's glands on histology and were strongly positive for the glucagon-like peptide-1 receptor. This case provides histopathological verification that duodenal 68Ga-DOTA-Exendin-4 uptake is caused by uptake in Brunner's glands and points to a potential relationship between bariatric surgery and Brunner's glands.
8 patients with papillary cancer (4 with metastases, 4 in remission), 7 follicular cancer patients (6 with metastases), 2 patients with anaplastic thyroid cancer, and 4 other non-medullary thyroid cancer patients all received an intravenous bolus injection of 220 MBq [111In-DTPA-D-Phe1]octreotide. Planar anterior and posterior n camera images of head-neck, chest and abdomen were obtained 24 and 48 h after injection. All primary cancers showed [111ln-DTPA-D-Phe1]octreotide uptake; none occurred in patients in remission. The results were compared with conventional radio-iodine scintigraphy in patients with metastasised, differentiated thyroid cancer.
