gastrins and Kidney-Neoplasms

Cholecystokinin subtype 2 receptors (CCK2R) are overexpressed in several human cancers, including medullary thyroid carcinoma. Gastrin and cholecystokinin (CCK) peptides that bind with high affinity and specificity to CCK2R can be used as carriers of radioactivity to CCK2R-expressing tumor sites. Several gastrin and CCK related peptides have been proposed for diagnostic imaging and radionuclide therapy of primary and metastatic CCK2R-positive human tumors. Their clinical application has been restricted to a great extent by their fast in vivo degradation that eventually compromises tumor uptake. This problem has been addressed by structural modifications of gastrin and CCK motifs, which, however, often lead to suboptimal pharmacokinetic profiles. A major enzyme implicated in the catabolism of gastrin and CCK based peptides is neutral endopeptidase (NEP), which is widely distributed in the body. Coinjection of the NEP inhibitor phosphoramidon (PA) with radiolabeled gastrin and other peptide analogs has been recently proposed as a new promising strategy to increase bioavailability and tumor-localization of radiopeptides in tumor sites. Specifically, co-administration of PA with the truncated gastrin analog [(111)In-DOTA]MG11 ([((111)In-DOTA)DGlu(10)]gastrin(10-17)) impressively enhanced the levels of intact radiopeptide in mouse circulation and has led to an 8-fold increase of CCK2R-positive tumor uptake in SCID mice. This increased tumor uptake, visualized also by SPECT/CT imaging, is expected to eventually translate into higher diagnostic sensitivity and improved therapeutic efficacy of radiolabeled gastrin analogs in CCK2R-expressing cancer patients.

Topics: Animals; Carcinoma, Neuroendocrine; Cholecystokinin; Gastrins; Gene Expression Regulation, Neoplastic; Glycopeptides; Humans; Kidney; Kidney Neoplasms; Ligands; Mice; Mice, SCID; Models, Chemical; Neoplasm Transplantation; Neoplasms; Neprilysin; Peptides; Radiopharmaceuticals; Receptor, Cholecystokinin B; Thyroid Neoplasms; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

We present a rare case of renal gastrinoma. To the best of our knowledge, only one case of renal gastrinoma has been reported in the literature so far. An African American male was diagnosed with Zollinger Ellison syndrome at the age of 15 years, when he underwent surgery for peritonitis secondary to duodenal ulcer perforation. Further evaluation was deferred and proton pump inhibitors were prescribed. Later evaluation showed a left renal mass. Serum gastrin levels were 4,307 pg/ml. A CAT scan of the abdomen showed 4- x 4-cm heterogeneous solid mass in the interpolar region of the left kidney with central hypodensity. Somatostatin scintigraphy confirmed a receptor-positive mass in the same location. Nephrectomy was done and the tumor was diagnosed on histopathological examination as a gastrinoma. At 6-month follow-up, gastrin levels were 72 pg/ml. After a follow-up of 6 years, the patient has no recurrent symptoms.

Topics: Adolescent; Diagnosis, Differential; Gastrinoma; Gastrins; Humans; Kidney; Kidney Neoplasms; Male; Nephrectomy; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

Gastrin and cholecystokinin (CCK) are two major regulatory peptides synthesized by human gut and brain tissues as well as by selected tumors, in particular gastrin-producing neuroendocrine tumors. In the present study we have evaluated gastrin and CCK gene expression in a group of primary human tumors, including neuronal, renal, and myogenic stem cell tumors, using in situ hybridization techniques. In addition, CCK-A and CCK-B receptors were evaluated in the same group of tumors with receptor autoradiography. Most tumors had gastrin messenger ribonucleic acid (mRNA): 10 of 11 medulloblastomas, 5 of 5 central primitive neuroectodermal tumors, 11 of 11 Ewing sarcomas, 8 of 10 neuroblastomas, 4 of 4 Wilms' tumors, 5 of 5 rhabdomyosarcomas, and 10 of 10 leiomyosarcomas. CCK mRNA was restricted predominantly to Ewing sarcomas (9 of 11) and leiomyosarcomas (5 of 10). CCK-A and CCK-B receptors were not frequently found in these tumors, except for leiomyosarcomas. These data suggest that gastrin and CCK may play a previously unrecognized role in this group of human stem cell tumors. If the increased gastrin mRNA indeed translates into increased gastrin production, measurement of gastrinemia may have a diagnostic significance in the early detection of these tumors. As these two hormones have been reported to act as potent growth factors, they may be of pathophysiological relevance for patients with such stem cell tumors.

Topics: Blotting, Northern; Brain Neoplasms; Cholecystokinin; Gastrins; Humans; In Situ Hybridization; Kidney Neoplasms; Leiomyosarcoma; Medulloblastoma; Neuroblastoma; Neuroectodermal Tumors, Primitive; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Rhabdomyosarcoma; RNA, Messenger

The role of gastrin in the control of growth of renal G401 cells isolated from a human nephroblastoma (Wilms' tumour) was investigated. G401 cell growth was enhanced in the presence of exogenous gastrin. Addition of anti-gastrin antibodies to serum-free medium significantly inhibited the growth of G401 cells. G401 cells contained the equivalent of 4.3 pg/10(6) cells of gastrin, and serum-free medium collected over 48 hr from G401 cells contained the equivalent of 38 ng/10(6) cells of gastrin, as determined by radioimmunoassay. Growth of G401 cells was inhibited in a concentration-related way by a variety of gastrin/CCK receptor antagonists. Devazepide and proglumide were, respectively, the most and the least potent inhibitors of G401 cell growth (potency order devazepide > L-365,260 = lorglumide > loxiglumide > benzotript > proglumide). These gastrin/CCK receptor antagonists had similar growth-inhibitory activities in human colonic adenocarcinoma HCT-116 cells. Growth of HCT-116 cells was stimulated to a lesser extent, as compared with G401 cells, by exogenous gastrin, and endogenous gastrin was not detectable in HCT-116 cells. The results are consistent with a role for a gastrin-like peptide in the control of growth of a renal cell line. The data suggest that gastrin/CCK receptor antagonists warrant further investigation as therapeutic agents for the control of gastrin-responsive tumours derived from outside, as well as inside, the gastrointestinal tract, including tumours derived from the kidney.

Topics: Benzamides; Benzodiazepinones; Cell Division; Devazepide; Gastrins; Humans; Indoles; Kidney Neoplasms; Meglumine; Phenylurea Compounds; Proglumide; Receptors, Cholecystokinin; Tumor Cells, Cultured; Wilms Tumor

Our experience with 47 sporadic gastrinomas suggests that no less than 85% of these tumors are located to the right of the superior mesenteric artery. This finding is unexpected because approximately 75% of insulinomas and glucagonomas are located to the left of the superior mesenteric artery. All of our extrapancreatic gastrinomas have been located to the right. These observations prompted us to determine if other extrapancreatic gastrinomas were also predominantly located to the right side. We searched the world's literature and found 10 cases of ovarian gastrinomas and one case of a renal gastrinoma. Nine of these remote extrapancreatic gastrinomas were located on the right side. This distribution of remote extrapancreatic gastrinomas is similar to our experience with peripancreatic gastrinomas. This unexpected right-sided preponderance of both remote and peripancreatic gastrinomas suggests a common origin for both.

Topics: Adult; Aged; Female; Gastrinoma; Gastrins; Humans; Kidney Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia; Ovarian Neoplasms; Secretin

Fifteen patients with Zollinger-Ellison syndrome followed at the National Institutes of Health with extensive metastatic disease had an actuarial 5-year survival of 20%. Therefore, in 1982 a prospective study to examine the effect and feasibility of removing all gross tumor in selected patients with extensive metastatic disease was instituted. Five patients with extensive metastatic gastrinoma confined to the abdomen in whom imaging studies suggested the possibility of complete surgical resection were entered into this study and underwent attempted complete surgical resection and chemotherapy with streptozotocin, doxorubicin, and 5-fluorouracil. Median follow-up was 24 months. Surgical resection of all gastrinoma was possible in 4/5 patients attempted. In one patient in whom all gross disease could not be resected, the residual tumor progressed and the patient died 19 months after operation. All four patients with all disease resected appeared to benefit since all of them had a significant reduction in antisecretory medications and are enjoying normal activity and work. Three patients have had no detectable tumor on follow-up, and two of these patients are clinically and biochemically "cured" with normal fasting gastrin levels and negative provocative gastrin tests at 14 and 32 months. Therefore, aggressive resection of metastatic disease in selected patients with malignant gastrinoma is recommended.

Topics: Abdominal Neoplasms; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cimetidine; Combined Modality Therapy; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Gastrins; Humans; Kidney Neoplasms; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Prognosis; Prospective Studies; Radiography; Ranitidine; Streptozocin; Zollinger-Ellison Syndrome

Genitourinary anomalies were looked for in patients with congenital hypertrophic pyloric stenosis. In a prospective series of 64 patients investigated by intravenous pyelography, 13 were abnormal (20.6%). In a retrospective series of 232 patients, 6 had anomalies of the upper urinary tract (2.7%). In this latter series the incidence of inguinal hernia (3.4%), undescended testes (3.0%), and hypospadias (0.9%) was determined. In another 10 patients urinary tract anomalies (5), urinary infection (2), and a significant family history (3) were found associated with congenital pyloric stenosis. As the incidence of these anomalies is greater than expected, which suggests an interrelationship, a hypothesis has been proposed linking genetic factors and the metabolism of gastrin with the etiology of congenital hypertrophic pyloric stenosis.

Topics: Female; Gastrins; Hernia, Inguinal; Humans; Hypertrophy; Kidney Neoplasms; Male; Prospective Studies; Pyloric Stenosis; Retrospective Studies; Urogenital Abnormalities; Wilms Tumor

Topics: Adult; Aged; Carcinoid Tumor; Cholinesterases; Esterases; Female; Fluorescent Antibody Technique; Gastrins; Histocytochemistry; Hormones; Humans; Immunochemistry; Kidney Neoplasms; Liver Neoplasms; Male; Microscopy, Electron; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Peptide Biosynthesis; Staining and Labeling

Topics: Adolescent; Adult; Animals; Catecholamines; Dogs; Epinephrine; Female; Gastrins; Humans; Kidney Neoplasms; Methods; Phenoxybenzamine; Pheochromocytoma; Radioimmunoassay; Time Factors