Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 51
Filtrar
1.
Regul Pept ; 96(3): 113-7, 2001 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-11111016

RESUMEN

INTRODUCTION: Neuroendocrine tumors often metastasize to the liver and present with disabling hormonal symptoms. Hepatic artery chemoembolization (HACE) combined with somatostatin therapy, pre-embolization, peri-embolization and post-embolization, at doses to control symptoms, is an aggressive approach that can relieve hormonal symptoms with minimal morbidity and mortality. METHODS: Chemoembolization was performed using 30 mg of adriamycin, 50 mg of mitomycin, 12 ml of hexabrix, 10 ml of ethiodol, and 360-500-microm particles. Pancreastatin, a split product of chromogranin A, was measured pre-HACE and post-HACE in all patients. RESULTS: Forty-three chemoebolization procedures were performed in 34 symptomatic patients from December 1995 to August 1999. Seventeen patients had intestinal primaries (50%), seven had pancreatic primaries (20%), five had bronchial primaries (15%), and five had unknown primaries (15%). Systemic pancreastatin levels were improved or stable in 31 patients (78%). Symptoms were improved in these 31 patients (78%). Systemic serotonin levels were improved or stable in 24 patients (60%). Radiographic improvement or stability was seen in 18 patients (45%). Procedural related morbidity included pain, fevers, nausea, vomiting, and transient elevations of liver function studies in 75-100% of patients. There was one procedural related mortality (2%). Less than 20% improvement in pancreastatin levels from baseline was associated with death in five of five patients (100%). This was not observed with serotonin levels. CONCLUSION: Measurement of serum pancreastatin levels is an easy and useful method to predict success in patients who undergo HACE plus somatostatin therapy for metastatic neuroendocrine tumors to the liver. This therapeutic approach is effective in relieving symptoms in 78% of patients, with minimal major morbidity or mortality.


Asunto(s)
Quimioembolización Terapéutica , Arteria Hepática , Tumores Neuroendocrinos/sangre , Tumores Neuroendocrinos/terapia , Hormonas Pancreáticas/sangre , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Quimioembolización Terapéutica/efectos adversos , Cromogranina A , Cromograninas/sangre , Cromograninas/metabolismo , Medios de Contraste/administración & dosificación , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Aceite Etiodizado/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Ácido Yoxáglico/administración & dosificación , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Masculino , Persona de Mediana Edad , Mitomicina/administración & dosificación , Mitomicina/farmacología , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/patología , Hormonas Pancreáticas/metabolismo , Serotonina/sangre
2.
Clin Chem ; 45(1): 29-34, 1999 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-9895334

RESUMEN

Gastrinomas and other gastrointestinal neuroendocrine tumors may occur sporadically or as part of the inherited syndrome multiple endocrine neoplasia type 1 (MEN1). Mutations in the recently identified MEN1 gene have been described in sporadic gastrinomas and insulinomas. This study describes techniques used to identify mutations in the MEN1 gene in DNA extracted from paraffin-preserved tissue. Two novel mutations are identified in the MEN1 gene from nine archived paraffin-embedded neuroendocrine tumors, demonstrating that retrospective genetic analysis can be used to identify mutations in the MEN1 gene from preserved tissue. Conditions are provided by which paraffin-embedded tissue can be used as a source of genetic material for sequence information of sufficient quality for mutational studies of the MEN1 gene. It should also be possible to apply this retrospective genetic analysis of paraffin-embedded tissue to other disease models.


Asunto(s)
Neoplasias Gastrointestinales/genética , Neoplasia Endocrina Múltiple Tipo 1/genética , Proteínas de Neoplasias/genética , Tumores Neuroendocrinos/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas , ADN de Neoplasias/análisis , Neoplasias Duodenales/genética , Neoplasias Duodenales/patología , Gastrinoma/genética , Gastrinoma/patología , Neoplasias Gastrointestinales/patología , Heterocigoto , Humanos , Insulinoma/genética , Insulinoma/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Mutación , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patología , Adhesión en Parafina , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología
3.
J Gastrointest Surg ; 2(1): 72-8, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9841971

RESUMEN

The long-term sequelae of pancreaticoduodenectomy are not completely understood. In the present study nutritional status, pancreatic function, and subjective quality-of-life parameters were evaluated in 45 patients who had previously undergone either pylorus-preserving pancreaticoduodenectomy (PPPD) or standard pancreaticoduodenectomy (SPD). Quality-of-life parameters, as measured by the Short Form-36 health survey, demonstrated no significant differences between the subgroups and normal control subjects in six of the eight domains for physical and mental health. Patients who had undergone SPD were noted to have significantly lower scores for general health and vitality than either age-matched control subjects or those who had undergone PPPD. No differences in nutritional parameters or indicators of pancreatic exocrine function between the two groups were identified. An elevated hemoglobin A1c value was seen in only one patient who was not diabetic preoperatively. Our data indicate that long-term survivors of pancreaticoduodenectomy generally feel as good as their normal counterparts, although SPD may result in some health satisfaction deficits. Nutritional status and pancreatic exocrine function are not improved in patients undergoing a pylorus-preserving procedure, and postoperative pancreatic endocrine dysfunction is unusual in both groups.


Asunto(s)
Pancreaticoduodenectomía , Actitud Frente a la Salud , Estudios de Casos y Controles , Estudios de Evaluación como Asunto , Femenino , Estudios de Seguimiento , Gastroenterostomía , Hemoglobina Glucada/análisis , Estado de Salud , Humanos , Yeyuno/cirugía , Masculino , Salud Mental , Persona de Mediana Edad , Estado Nutricional , Páncreas/fisiopatología , Pancreaticoduodenectomía/efectos adversos , Pancreaticoduodenectomía/métodos , Pancreaticoduodenectomía/psicología , Pancreatoyeyunostomía , Satisfacción del Paciente , Antro Pilórico/cirugía , Píloro/cirugía , Calidad de Vida , Sobrevivientes , Resultado del Tratamiento
4.
Med Hypotheses ; 50(6): 501-6, 1998 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9710324

RESUMEN

Long-acting somatostatin analogs have recently become supplemental drugs in the treatment of neurofibroma because of their marked tumor growth inhibitory effect. Somatostatin is currently under extended evaluation in other cancers as a possible supplemental drug to the treatment protocols in use. The mode of action is not known. Somatostatin has been shown to cause glucose intolerance by inhibiting glucose-6-phosphate dehydrogenase (G6PD) in fish liver. Recent data generated in our laboratory indicate that it is this pathway and the transketolase reactions of the pentose cycle (PC) which are directly involved in the ribose synthesis process of pancreatic adenocarcinoma cells. In cell culture, somatostatin alone inhibited glucose carbon recycling through the PC by 5.7%, which was increased to 19.8% in combination with oxythiamine, a competitive inhibitor of transketolase. Oxythiamine produced strong apoptosis in in-vitro hosted tumor cells. We hypothesize that somatostatin- and oxythiamine-induced antiproliferative action is mediated by the inhibition of G6PD, transketolase, or both.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Vía de Pentosa Fosfato/efectos de los fármacos , Somatostatina/farmacología , Animales , División Celular/efectos de los fármacos , Glucosa/metabolismo , Glucosafosfato Deshidrogenasa/metabolismo , Humanos , Modelos Biológicos , Transcetolasa/metabolismo
5.
Anticancer Res ; 18(1B): 595-602, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9568183

RESUMEN

The objectives of this review are to (a) explain the mechanism by which thiamine (vitamin B1) promotes nucleic acid ribose synthesis and tumor cell proliferation via the nonoxidative transketolase (TK) pathway; (b) estimate the thiamine intake of cancer patients and (c) provide background information and to develop guidelines for alternative treatments with antithiamine transketolase inhibitors in the clinical setting. Clinical and experimental data demonstrate increased thiamine utilization of human tumors and its interference with experimental chemotherapy. Analysis of RNA ribose indicates that glucose carbons contribute to over 90% of ribose synthesis in cultured cervix und pancreatic carcinoma cells and that ribose is synthesized primarily through the thiamine dependent TK pathway (> 70%). Antithiamine compounds significantly inhibit nucleic acid synthesis and tumor cell proliferation in vitro and in vivo in several tumor models. The medical literature reveals little information regarding the role of the thiamine dependent TK reaction in tumor cell ribose production which is a central process in de novo nucleic acid synthesis and the salvage pathways for purines. Consequently, current thiamine administration protocols oversupply thiamine by 200% to 20,000% of the recommended dietary allowance, because it is considered harmless and needed by cancer patients. The thiamine dependent TK pathway is the central avenue which supplies ribose phosphate for nucleic acids in tumors and excessive thiamine supplementation maybe responsible for failed therapeutic attempts to terminate cancer cell proliferation. Limited administration of thiamine and concomitant treatment with transketolase inhibitors is a more rational approach to treat cancer.


Asunto(s)
Neoplasias/tratamiento farmacológico , Tiamina/efectos adversos , Tiamina/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , División Celular , Guías como Asunto , Humanos , Ácidos Nucleicos/biosíntesis , Tiamina/química , Transcetolasa/metabolismo
6.
Surgery ; 123(3): 315-20, 1998 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-9526524

RESUMEN

BACKGROUND: Streptozotocin-diabetes prevents induction of pancreatic tumors in several animal models and inhibits the growth of established human pancreatic cancer implants in nude mice. However, it also promotes growth of the hamster pancreatic cancer cell line, H2T, in the Syrian hamster. To test the hypothesis that these contradictory effects are due to tumor host differences, the growth of the H2T cell line was examined in the streptozotocin-diabetic nude mouse. METHODS: H2T cells were implanted subcutaneously into streptozotocin-diabetic nude mice (n = 10) and untreated control mice (n = 10). After 21 days, tumors were excised and weighed. Plasma insulin and somatostatin were determined by radioimmunoassay. RESULTS: After 3 weeks, tumors in the control group weighed 118 mg and tumors in the diabetic group weighed 28 mg (p < 0.001). Plasma insulin was significantly decreased in the streptozotocin-treated animals compared with control animals (insulin, 23 microU/ml vs 31 microU/ml; p < 0.001). In contrast, somatostatin was significantly elevated in the streptozotocin-diabetic group compared with the control group (somatostatin, 179 pg/ml versus 54 pg/ml, p < 0.001). Competitive binding studies revealed specific cell surface receptors for insulin (Kd, 15.5 nmol/L), and somatostatin (Kd, 2.5 nmol/L) on the H2T cells. In an in vitro cell proliferation assay, cell division was promoted by insulin (p < 0.01, maximum +11%) and inhibited by somatostatin (p < 0.01, maximum -18%). CONCLUSIONS: The variable effect of streptozotocin-diabetes on pancreatic cancer growth is due to differences in the tumor host. The growth of pancreatic cancer, particularly in streptozotocin-diabetic nude mice, may be influenced by gut peptides in a receptor-dependent fashion.


Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Neoplasias Pancreáticas/patología , Animales , Peso Corporal , Cricetinae , Mesocricetus , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias Pancreáticas/complicaciones , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Receptores de Glucagón/metabolismo , Receptores de Somatostatina/metabolismo , Trasplante Heterólogo , Células Tumorales Cultivadas
8.
Med Hypotheses ; 50(1): 55-9, 1998 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-9488183

RESUMEN

Pentose phosphate pathways (PPP) are considered important in tumor proliferation processes because of their role in supplying tumor cells with reduced NADP and carbons for intracellular anabolic processes. Direct involvement of PPP in tumor DNA/RNA synthesis is not considered as significant as in lipid and protein syntheses. Currently, PPP activity in tumor cells is measured by lactate production, which shows a moderate activity: about 4% to 7% compared with glycolysis. Recent data generated in our laboratory indicate that PPP are directly involved in ribose synthesis in pancreatic adenocarcinoma cells, through oxidative steps (< 31%) and transketolase reactions (69%). These findings raise serious questions about the adequacy of lactate in measuring PPP activity in tumors. We hypothesize that ribose, not lactate, is the major product of PPP in tumor cells. Control of both oxidative and nonoxidative PPP may be critical in the treatment of cancer. PPP are substantially involved in the proliferation of human tumors, which raises the prospect of new treatment strategies targeting specific biochemical reactions of PPP by hormones related to glucose metabolism, controlling thiamine intake, the cofactor of the nonoxidative transketolase PPP reaction, or treating cancer patients with antithiamine analogues.


Asunto(s)
Glucosa/metabolismo , Enfermedades Metabólicas/metabolismo , Neoplasias/etiología , Neoplasias/metabolismo , Vía de Pentosa Fosfato , Ribosa/biosíntesis , Adenocarcinoma/etiología , Adenocarcinoma/metabolismo , Glucólisis , Humanos , Modelos Biológicos , Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/metabolismo , ARN Neoplásico/biosíntesis
9.
Cancer Res ; 58(2): 237-40, 1998 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-9443399

RESUMEN

Neoplasms of the endocrine pancreas are extremely rare, and molecular mechanisms influencing their development are poorly understood. Nevertheless, gastrinomas have become a paradigm for the study of hormonally active tumors. In the present study, 12 gastrinoma and nonfunctioning pancreatic neuroendocrine tumor specimens were evaluated for genetic alterations of the p16/MTS1 tumor suppressor gene. DNA extracted from microdissected portions of paraffin-embedded tumor sections were examined for mutations and homozygous deletions using "Cold" single-strand conformation polymorphism and semiquantitative PCR-based analyses, respectively. Samples were also analyzed for the presence of 5' CpG island hypermethylation using methylation-specific PCR. The p16/MTS1 gene was found to be homozygously deleted in 41.7% of tumors and methylated in 58.3%, but no mutations were identified by single-strand conformation polymorphism analyses. Overall, 91.7% of the specimens demonstrated inactivating alterations in p16/MTS1. These data suggest that transcriptional silencing of p16/MTS1 is a frequent event in these rare and poorly understood tumors.


Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Gastrinoma/genética , Eliminación de Gen , Genes p16/genética , Tumores Neuroendocrinos/genética , Neoplasias Pancreáticas/genética , Mutación Puntual , Islas de CpG , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Metilación de ADN , Cartilla de ADN/química , ADN de Neoplasias/análisis , Gastrinoma/metabolismo , Gastrinoma/patología , Humanos , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Reacción en Cadena de la Polimerasa
10.
Int J Pancreatol ; 24(3): 169-80, 1998 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9873951

RESUMEN

CONCLUSION: Gastrointestinal hormones and their antagonists can alter the growth of pancreatic adenocarcinoma in vitro and in vivo. The potential clinical benefit of this approach deserves further study. BACKGROUND: Epithelial cell growth is normally under hormonal control. Hormones also affect the growth of many epithelial cancers, and this fact is used to modify tumor growth. Pancreatic epithelial cell growth is under the influence of gastrointestinal hormones. This article reviews experiments designed to determine the effect of gastrointestinal hormones on the growth of pancreatic adenocarcinoma. METHODS: Eighty-eight articles were identified from a Medline search using the terms pancreatic adenocarcinoma and the individual names of gastrointestinal hormones. The experimental design and results of these studies are reviewed. RESULTS: In general, somatostatin, vasoactive intestinal polypeptide, pancreatic polypeptide, and pancreastatin inhibit pancreatic adenocarcinoma growth. Cholecystokinin, secretin, bombesin, gastrin, EGF, TGF-alpha, insulin, and IGF-1 have a growth-promoting effect.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Hormonas Gastrointestinales/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/patología , Animales , Quimioterapia Adyuvante , Hormonas Gastrointestinales/efectos adversos , Inhibidores de Crecimiento/uso terapéutico , Humanos , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias Hormono-Dependientes/patología , Neoplasias Pancreáticas/patología , Células Tumorales Cultivadas
11.
J Gastrointest Surg ; 2(6): 580-3; discussion 584, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-10457317

RESUMEN

Laparoscopic surgery for malignancy has been complicated by port-site recurrences. The exact mechanism has yet to be defined. In vitro studies suggest that carbon dioxide-induced tumor cell aerosolization may play a role. We have attempted to document this in a human model. Patients scheduled for elective laparoscopy underwent port placement and abdominal insufflation with carbon dioxide. A suction trap was then filled with 40 cc of normal saline solution and attached to an insufflation site on the port. The carbon dioxide effluent was directed through the saline. The specimen was concentrated, resuspended, and transferred to a slide. A Papanicolaou stain was used. Thirty-five specimens were obtained. Fifteen patients (37%) had malignant disease, which was metastatic in eight. Five patients had carcinomatosis. In two of those with carcinomatosis, staining revealed a large number of malignant cells. Malignant cells were not found in any other patients. In two patients, however, aerosolized mesothelial cells were identified. Follow-up ranged from 2 to 7 months. One patient who displayed cellular aerosolization developed a port-site recurrence. We conclude that malignant cells are aerosolized but only during laparoscopy in the presence of carcinomatosis. It is unlikely that tumor cell aerosolization contributes significantly to port-site metastasis.


Asunto(s)
Aerosoles , Laparoscopía/efectos adversos , Recurrencia Local de Neoplasia/etiología , Dióxido de Carbono , Humanos , Laparoscopía/métodos , Siembra Neoplásica , Neumoperitoneo Artificial
12.
Endocr Pract ; 4(6): 378-81, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-15251712

RESUMEN

OBJECTIVE: To report on the diagnosis of ectopic corticotropin (adrenocorticotropic hormone [ACTH])-producing bronchial carcinoid tumor by indium-111 pentetreotide (octreotide scan) scintigraphy. METHODS: We present a case of ectopic ACTH syndrome caused by an occult bronchial carcinoid tumor arising in a lymph node and review the pertinent literature. RESULTS: Biochemical diagnosis of ACTH syndrome can be difficult, and conventional imaging modalities often do not demonstrate these small carcinoid tumors. After biochemical proof of the presence of ectopic ACTH syndrome in our patient, conventional radiographic studies did not demonstrate any lesions. An octreotide scan showed a lesion in the lung, which was confirmed surgically. ACTH values returned to normal after resection of the lesion, and octreotide scans confirmed the completeness of surgical resection. The carcinoid tumor originated in a lymph node outside the bronchus. The differential diagnosis of ACTH syndrome, the localization of ectopic ACTH-producing tumors, the bronchial carcinoids, and the uniqueness of the carcinoid tumor arising in a lymph node are briefly discussed. CONCLUSION: Octreotide scintigraphy is useful in localizing occult carcinoid tumors and can be used in the follow-up of patients after successful removal of these tumors.

13.
Cancer Res ; 57(19): 4242-8, 1997 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-9331084

RESUMEN

This study investigates the significance of the glucose-6-phosphate dehydrogenase (G6PD) catalyzed oxidative and the transketolase (TK) catalyzed nonoxidative pentose cycle (PC) reactions in the tumor proliferation process by characterizing tumor growth patterns and synthesis of the RNA ribose moiety in the presence of respective inhibitors of G6PD and TK. Mass spectra analysis of 13C-labeled carbons revealed that these PC reactions contribute to over 85% of de novo ribose synthesis in RNA from [1,2-(13)C]glucose in cultured Mia pancreatic adenocarcinoma cells, with the fraction synthesized through the TK pathway predominating (85%). Five days of treatment with the TK inhibitor oxythiamine (OT) and the G6PD inhibitor dehydroepiandrosterone-sulfate (0.5 microM each) exerted a 39 and a 23% maximum inhibitory effect on cell proliferation in culture, which was increased to 60% when the two drugs were administered in combination. In vivo testing of 400 mg/kg OT or dehydroepiandrosterone-sulfate in C57BL/6 mice hosting Ehrlich's ascitic tumor cells revealed a 90.4 and a 46% decrease in the final tumor mass after 3 days of treatment. RNA ribose fractional synthesis through the TK reaction using metabolites directly from glycolysis declined by 9.1 and 23.9% after OT or the combined treatment, respectively. Nonoxidative PC reactions play a central regulating role in the carbon-recruiting process toward de novo nucleic acid ribose synthesis and cell proliferation in vitro and in vivo. Therefore, enzymes or substrates regulating the nonoxidative synthesis of ribose could also be the sites to preferentially target tumor cell proliferation by new anticancer drugs.


Asunto(s)
Carcinoma de Ehrlich/metabolismo , Sulfato de Deshidroepiandrosterona/farmacología , Glucosafosfato Deshidrogenasa/metabolismo , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Oxitiamina/farmacología , Vía de Pentosa Fosfato/efectos de los fármacos , Ribosa/biosíntesis , Transcetolasa/metabolismo , Triosa-Fosfato Isomerasa/metabolismo , Animales , Carcinoma/patología , División Celular/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos C57BL , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Pancreáticas/patología , ARN Neoplásico/metabolismo , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/metabolismo
14.
Surgery ; 121(4): 392-7, 1997 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-9122868

RESUMEN

BACKGROUND: Dehydroepiandrosterone-sulfate (DHEA-S) is a potent inhibitor of glucose-6 phosphate dehydrogenase, the rate limiting enzyme of the hexose monophosphate shunt, a biochemical pathway that provides substrate for DNA synthesis in neoplastic tissue. DHEA-S has been shown to inhibit the growth of neoplasms arriving from human skin, lung, colon, and mammary tissue. This study evaluates the effect of DHEA-S on human pancreatic cancer cell lines in vitro and in vivo. METHODS: In vitro, the human pancreatic adenocarcinoma cell lines MiaPaCa-2, Capan-1, Capan-2, CAV and Panc-1 were treated with concentrations of 1.9 mumol/L to 1000 mumol/L DHEA-S in 1% dimethylsulfoxide (DMSO) for 5 consecutive days. Cell proliferation was determined by a nonradioactive cell proliferation assay and compared with DMSO treated controls. In vivo testing was performed by inoculating two cell lines, MiaPaCa-2 and Panc-I, into the flank of 40 male nude athymic mice in four study groups. After 1 week of growth, 667 mg/kg DHEA-S in 1% DMSO or 0.2 ml 1% DMSO alone in the control group was administered by daily intraperitoneal injection. Body weight and tumor size was recorded weekly, and tumor weight was measured after 3 weeks of treatment. RESULTS: In vitro cell proliferation was decreased in the five cell lines by 36% to 62% of controls (p < 0.001) at 500 mumol/L DHEA-S. In vivo, after 2 weeks, tumor size was only 76% (p < 0.008) and 67% (p < 0.005) of the controls. After 3 weeks of treatment, tumor size was 73% (p < 0.001) and 53% (p < 0.001) of controls, and tumor weight was decreased by 73% in MiaPaCa-2 (p < 0.001) and 66% in Panc-1 (p < 0.001). Radioimmunoassay measurements of DHEA-S and testosterone from DHEA-S treated mouse plasma showed a significant increase in circulating levels of these hormones. CONCLUSIONS: DHEA-S achieves high serum levels after intraperitoneal injection without elevation of serum testosterone levels and produces no significant toxicity. Treatment with DHEA-S results in a significant reduction of proliferation of human pancreatic cancer cells in culture and when grown as subcutaneous tumors in athymic nude mice.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Sulfato de Deshidroepiandrosterona/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/sangre , Adenocarcinoma/patología , Animales , División Celular/efectos de los fármacos , Sulfato de Deshidroepiandrosterona/sangre , Humanos , Ratones , Ratones Desnudos , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/patología , Células Tumorales Cultivadas
15.
Surgery ; 120(2): 234-40; discussion 240-1, 1996 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-8751588

RESUMEN

BACKGROUND: Somatostatin inhibits proliferation of many solid tumors. The current study examines whether inhibition of the growth of pancreatic cancer by the somatostatin analog, octreotide, requires tumor expression of somatostatin receptors. METHODS: We studied five human pancreatic cancer cell lines, Capan-1, Capan-2, CAV, MIA PaCa-2, and Panc-1. Solid tumors were established in nude mice (n = 20/cell line) by flank injection of tumor cells. Subcutaneous octreotide (500 micrograms/kg/day) was administered by osmotic pumps to 10 of the animals in each group, and the other 10 received control infusions of saline solution. On day 36, the tumors were excised and weighed. Plasma levels of the putative trophic peptides cholecystokinin, epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and insulin were assessed by radioimmunoassay. Each of the five cell lines was assayed for the presence of cell surface somatostatin receptors by using whole cell competitive binding assays with 125I-somatostatin. Expression of the somatostatin receptor subtype-2 (SSR2) gene was determined with reverse transcriptase-polymerase chain reactions. Southern blot hybridization was used to assess the presence of the SSR2 gene. RESULTS: Octreotide inhibited tumor growth in the MIA PaCa-2 group (512 +/- 75 mg control versus 285 +/- 71 mg treated; p < 0.05) but had no significant effect on tumor weight in the other four cell lines. Plasma levels of cholecystokinin, epidermal growth factor, insulin-like growth factor-1, and insulin were not altered by chronic octreotide infusion. Cell surface somatostatin receptors and SSR2 gene expression were detected only in the MIA PaCa-2 tumors. The gene for the SSR2 receptor was found in all five tumor lines. CONCLUSIONS: Octreotide-mediated inhibition of pancreatic cancer growth is dependent on expression of somatostatin receptors. The expression of somatostatin receptors should be considered in the design and interpretation of clinical trials with somatostatin analogs for treatment of pancreatic cancer.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Octreótido/farmacología , Receptores de Somatostatina/genética , Adenocarcinoma , Animales , Secuencia de Bases , Unión Competitiva/fisiología , Southern Blotting , División Celular/efectos de los fármacos , Colecistoquinina/sangre , ADN de Neoplasias/análisis , Factor de Crecimiento Epidérmico/sangre , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Ratones , Ratones Desnudos , Datos de Secuencia Molecular , Neoplasias Pancreáticas , Péptidos/sangre , Reacción en Cadena de la Polimerasa , Células Tumorales Cultivadas/citología , Células Tumorales Cultivadas/fisiología
16.
J Surg Res ; 63(1): 310-3, 1996 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-8661216

RESUMEN

Type-II diabetes is a risk factor for pancreatic cancer. In addition, diabetic patients present with more advanced tumors and have shortened survival compared to stage-matched counterparts. We hypothesize that the diabetic endocrine milieu, particularly elevated plasma insulin, favors pancreatic cancer growth. This study examines six human pancreatic cancer cell lines for the presence of insulin receptors and the influence of insulin on tumor proliferation. Classical competitive binding assays are performed using [125I insulin. Cell proliferation assays are conducted over 3 days on cultured cell lines (n = 6 replicates) with increasing concentrations of insulin. Insulin receptors are demonstrated on all six cell lines and dose dependent increases in cell proliferation (15-120% of control) are demonstrated in response to insulin. Patients with type-II diabetes hypersecrete insulin. The presence of high-affinity insulin receptors and dose dependent increases in pancreatic cancer cell proliferation with insulin supports the hypothesis that insulin may be an important tumor growth promoter in diabetes, particularly if paracrine mechanisms are involved. Additional study is required to determine whether other islet peptides altered in diabetes influence tumor growth and whether elevated plasma insulin favors pancreatic cancer induction.


Asunto(s)
División Celular/efectos de los fármacos , Insulina/farmacología , Insulina/fisiología , Receptor de Insulina/metabolismo , Adenocarcinoma , Unión Competitiva , Línea Celular , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Insulina/metabolismo , Cinética , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/patología , Factores de Riesgo , Factores de Tiempo , Células Tumorales Cultivadas
17.
Surgery ; 118(6): 1105-13; discussion 1113-4, 1995 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-7491530

RESUMEN

BACKGROUND: The present study evaluates 111In-pentetreotide scanning as a method for detection of gastrinomas. Operative findings serve as the benchmark for comparison of the efficacy of 111In-pentetreotide versus conventional imaging studies. METHODS: Twelve patients (seven female and five male; age, 37 to 80 years) with histologic confirmation of gastrinoma underwent thin section dynamic computed tomography (CT) scanning and 111In-pentetreotide scanning. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 111In-pentetreotide and CT scanning are compared on the basis of tumor size and location. RESULTS: Thirty discrete foci of intrahepatic and extrahepatic tumors were detected at operation. CT scanning detected three of nine pancreaticoduodenal lesions, whereas eight of these nine extrahepatic primary tumors were imaged by 111In-pentetreotide scanning. No false-positive 111In-pentetreotide scans were noted. The sensitivity of CT scanning for detection of metastatic disease was 56% versus 94% for the 111In-pentetreotide scan. Successful CT imaging was highly dependent on tumor size. No tumor smaller than 1 cm was imaged by CT, whereas four of seven lesions greater than 1 cm were imaged by 111In-pentetreotide scintigraphy. The smallest gastrinoma imaged by 111In-pentetreotide scanning was a 4 mm duodenal tumor. CONCLUSIONS: 111In-pentetreotide scanning was superior to CT scanning for localizing gastrinomas. Further studies are required to determine whether 111In-pentetreotide scans will complement or replace traditional imaging methods.


Asunto(s)
Gastrinoma/diagnóstico por imagen , Radioisótopos de Indio , Somatostatina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Duodenales/diagnóstico , Neoplasias Duodenales/diagnóstico por imagen , Femenino , Gastrinoma/diagnóstico , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/diagnóstico por imagen , Metástasis Linfática/diagnóstico , Metástasis Linfática/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/diagnóstico por imagen , Cintigrafía , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos X
18.
Surgery ; 118(2): 453-7; discussion 457-8, 1995 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-7638764

RESUMEN

BACKGROUND: Epidemiologic and animal studies have linked pancreatic cancer growth with both diabetes and fat intake. This study examined the influence of insulin treatment on pancreatic cancer growth in diabetes. Diabetes-induced elevations in levels of glucose and free fatty acids were correlated with enhanced tumor growth both in vivo and in vitro. METHODS: Hamsters were divided into three groups: control (n = 15), streptozocin-diabetic (n = 20), or insulin-treated diabetic (n = 20). Diabetes was induced with streptozocin and treated with a continuous subcutaneous infusion of insulin delivered via osmotic pumps. Five x 10(5) H2T hamster pancreatic cancer cells were implanted into the cheek pouch. Levels of plasma glucose and fatty acids were measured, and their effect on H2T cell division was assessed in vitro with a spectrophotometric cell proliferation assay. RESULTS: Levels of plasma glucose and fatty acids were elevated in streptozocin-diabetic animals and normalized with insulin treatment. After 21 days of growth, tumor weight was 36 mg in the control group, 156 mg in the diabetic group (p < 0.01 versus other groups), and 33 mg in the insulin-treated diabetic group. In vitro dose-dependent promotion of cell growth was shown for glucose (250%), linoleic acid (287%), linolenic acid (169%), and oleic acid (98%). CONCLUSIONS: Insulin ameliorated enhanced tumor growth in this model of diabetes. Glucose and free fatty acids mobilized during diabetes may serve as fuel for established pancreatic cancers.


Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Insulina/farmacología , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/patología , Animales , Glucemia/análisis , Cricetinae , Diabetes Mellitus Experimental/sangre , Ácidos Grasos/sangre , Masculino , Mesocricetus , Células Tumorales Cultivadas
19.
Semin Nucl Med ; 25(3): 251-61, 1995 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-7570044

RESUMEN

Somatostatin, a naturally occurring 14-amino acid peptide, can be thought of as an anti-growth hormone and functional down-regulator of sensitive tissue. Most neuroendocrine tumors seem to possess somatostatin receptors in sufficient abundance to allow successful scintigraphic imaging with radiolabeled somatostatin congeners. Several of these, including Indium-III-DTPA Pentetreotide (Octreoscan [Mallinckrodt Medical, St. Louis, MO]), which was approved for clinical use by the Food and Drug Administration in June 1994, have been of considerable value in scintigraphically identifying various neuroendocrine tumors. The Octreoscan compares favorably with other imaging modalities. The success of somatostatin receptor imaging in evaluating patients with suspected neuroendocrine tumors, including identifying otherwise radiographically occult lesions, has resulted in ranking somatostatin receptor imaging as the prime imaging procedure in patients with suspected neuroendocrine tumors at The Ohio State University.


Asunto(s)
Radioisótopos de Indio , Tumores Neuroendocrinos/diagnóstico por imagen , Octreótido/análogos & derivados , Ácido Pentético/análogos & derivados , Receptores de Somatostatina/análisis , Humanos , Dosis de Radiación , Cintigrafía
20.
J Surg Res ; 58(6): 754-8, 1995 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-7791356

RESUMEN

Streptozotocin diabetes prevents induction of pancreatic tumors in several animal models, suggesting a pivotal role for islet cell products in the pathogenesis of pancreatic cancer. To test the hypothesis that altered gastrointestinal peptide levels in streptozotocin diabetes influence tumor growth, human pancreatic cancer cells (MIA PaCa-2) were implanted subcutaneously into streptozotocin diabetic nude mice. After 3 weeks, tumors in the control group weighed 43 mg and tumors in the diabetic group weighed 12 mg (P < 0.001). Plasma insulin and IGF-1 levels were significantly decreased in the streptozotocin-treated animals compared to those of control (insulin: 23 microU/ml vs 31 microU/ml, P < 0.001; IGF-1: 254 ng/ml vs 324 ng/ml, P < 0.001). In contrast, somatostatin and glucagon were significantly elevated in the streptozotocin diabetic group relative to control levels (somatostatin: 179 pg/ml vs 54 pg/ml, P < 0.001; glucagon: 290 pg/ml vs 134 pg/ml, P < 0.001). Competitive binding studies revealed specific cell surface receptors for insulin (Kd = 15.5 nM), IGF-1 (Kd = 30.0 nM), and somatostatin (Kd = 2.5 nM) on the MIA PaCa-2 cells. Receptors for glucagon were absent. In an in vitro cell proliferation assay, cell division was promoted by insulin (P < 0.01, max + 11%) and IGF-1 (P < 0.01, max + 10%). Somatostatin inhibited cell division (P < 0.01, max - 18%). No effect was seen with glucagon. The growth of pancreatic cancer, particularly in diabetes, may be influenced by gut peptides in a receptor-dependent fashion.


Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Hormonas Gastrointestinales/sangre , Neoplasias Pancreáticas/patología , Animales , División Celular , Glucagón/sangre , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Ratones , Somatostatina/sangre , Estreptozocina , Células Tumorales Cultivadas
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA