PubMed · 6258700
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D J Sanders, C W Venables. 1981. Secretin provocation tests.. https://doi.org/10.1002/bjs.1800680324
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BACKGROUND: The unsatisfactory control of neuroendocrine tumor growth with chemotherapy and/or interferon (IFN-2a) stimulated us to investigate the role of the somatostatin analogue octreotide (SMS 201.995), which is reported to be highly effective in controlling carcinoid syndrome symptoms. Octreotide has been used in a wide range of doses, and it was postulated that higher doses might lead to an objective response. METHODS: The aim of the present multicenter Phase II study was to determine the safety and efficacy of SMS 201.995 in controlling carcinoids and other neuroendocrine tumors. Fifty-eight patients were treated subcutaneously with 2 sequential doses of the drug (Sandostatina, Sandoz, Inc., S.b.A. Pharmaceuticals, Basel, Switzerland). The first 23 patients received 500 micrograms 3 times a day and the remaining 35 patients received 1000 micrograms 3 times a day. The treatment was continued until the tumor progressed. RESULTS: All of the patients were adequately treated and evaluated. The predominant histotype was carcinoid, although there were instances of medullary thyroid carcinoma, pancreatic islet cell tumors, and Merkel cell carcinoma. Carcinoid syndrome was documented in 16 patients and abnormal urinary 5-hydroxyindoloacetic acid excretion in 15. The median treatment duration was 5 months (range, 2-31 months). The responses were evaluated in three categories: tumor regression for tumor growth control, symptom response, and biochemical response. There was an effect on tumor growth in two patients with carcinoids. Symptomatic control was achieved in 73% of patients and a biochemical response in 77% of patients. In twenty-seven patients, the disease stabilized for at least 6 months (range, 6-32+). The median survival time for all patients was 22 months (range, 1-32+). CONCLUSIONS: In terms of tumor regression, octreotide is disappointing (partial response: 3%); symptomatic response and biochemical control are satisfactory. These data confirm that somatostatin analogues are comparable to interferons in the treatment of carcinoid syndrome, although other efforts are necessary to control tumor regression.
We report the histological, immunohistochemical and ultrastructural changes in mice containing a chimeric glucagon-simian virus 40 T antigen (SV40Tag) gene. Transgene expression was detected in endocrine cells of pancreas, small and large intestine. Hyperplasia of glucagon-containing cells developed in pancreas and large bowel by gestational day 19. In large bowel, hyperplastic cells increased in number postnatally and invasive carcinomas were identified at 4 weeks; several animals had lymph node metastases. In contrast, no pathology was detected in the small bowel in any of the transgenic mice. Colonic tumours expressed SV40Tag, proglucagon-derived peptides and peptide YY (PYY); scattered cells contained cholecystokinin or glycoprotein hormone alpha-subunit. Somatostatin or serotonin was also detected in some tumours. By electron microscopy, the colonic tumours retained features of endocrine differentiation, but secretory granules were smaller than those of non-tumorous intestinal glucagon-producing L cells. In postnatal pancreas, atypical cells containing SV40Tag and glucagon were initially clustered at the periphery of islets; this atypical hyperplasia progressed to neoplasia by 11-12 weeks. Some neoplastic pancreatic cells contained glucagon, PYY or vasoactive intestinal peptide immunopositivity, but most were negative for all peptides; they contained immunoreactivity for tyrosine hydroxylase and by electron microscopy, pancreatic tumour cells had neuronal features. Pancreatic polypeptide was not detected in the non-tumorous islets of transgenic animals. This line of transgenic mice provides a model for the analysis of endocrine tumour progression in the gut and pancreas.
A communication-deficient cell line (RIN cells, derived from a rat islet tumour), stably transfected with cDNA coding for rat connexin43 (Cx43), was chosen to further assess the mechanism of voltage gating of Cx43 gap junction channels. The experiments were carried out on preformed cell pairs using a dual whole-cell, voltage-clamp method. The junctional current, Ij, revealed a time- and voltage-dependent inactivation at transjunctional voltages Vj>+/-40 mV. When an asymmetrical pulse protocol was used (in cell 1 the holding potential was maintained, in cell 2 it was altered to establish a variable Vj), the channels exhibited an asymmetrical gating behaviour: Vj,0=-73.7 mV and 65.1 mV for negative and positive Vj, respectively (Vj at which Ij is half-maximally inactivated); gj(min)=0.34 and 0.29 (normalized minimal conductance); tau = 350 ms and 80 ms at Vj=100 mV (time constant of Ij inactivation). Hence, these parameters were more sensitive to positive Vj values. When a symmetrical pulse protocol was used (the holding potentials in cell 1 and cell 2 were altered simultaneously in steps of equal amplitude but of opposite polarity), the Vj -dependent asymmetries were absent: Vj,0=-60.5 and 59.5; gj (min)=0.27 and 0.29; tau =64 ms and 47 ms at 100mV. Putative explanations for these observations are discussed. A possibility is that the number of channels alters with the polarity of Vj.