Control of Growth in Neuroendocrine Gastro-Enteropancreatic Tumours

Arnold, R.; Frank, M

doi:10.1159/000201400

Cited by 12 publications

(7 citation statements)

References 7 publications

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“…Somatostatin and its stable analog suppress the growth of various cancer cells, including neuroendocrine tumors that express somatostatin receptors (2,3). The evidence indicates that direct antiproliferative effects of somatostatin and its analogs are mediated by specific cell surface receptors.…”

mentioning

confidence: 99%

Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238

Benali

Cordelier

Calise

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

101

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The sst2 somatostatin receptor mediates the antiproliferative effects of somatostatin analogs. The present study demonstrates that stable expression of sst2 in the hamster pancreatic cancer cells PC-1 and PC-1.0 activates an autocrine negative loop leading to an in vitro inhibition of cell proliferation. In vivo studies conducted in Syrian golden hamsters after orthotopic implantation of PC-1.0 cells showed that both tumor growth and metastatic progression of allografts containing 100% of sst2-expressing cells were significantly inhibited for up to 20 days after implantation, as compared with control allografts that did not express sst2. A local antitumor bystander effect was observed after induction of mixed tumors containing a 1:3 ratio of sst2-expressing cells to control cells. Tumor volume and incidence of metastases of mixed tumors were significantly reduced at day 13 post implantation. This effect decreased with time as at day 20, growth of mixed tumors was similar to that of control tumors. After administration of the cytotoxic somatostatin conjugate AN-238 on day 13, antitumor bystander effect observed in mixed tumors was significantly extended to day 20. We also observed that in vitro invasiveness of sst2-expressing PC-1.0 cells was significantly reduced. Tyrosine dephosphorylation of E-cadherin may participate in restoring the E-cadherin function, reducing in turn pancreatic cancer cell motility and invasiveness. This dephosphorylation depends on the tyrosine phosphatase src homology 2-containing tyrosine phosphatase 1 (SHP-1) positively coupled to sst2 receptor. The inhibitory effect of sst2 gene expression on pancreatic cancer growth and invasion combined with chemotherapy with targeted cytotoxic somatostatin analog administration provides a rationale for a therapeutic approach to gene therapy based on in vivo sst2 gene transfer.bystander effect ͉ tumor invasion ͉ targeted chemotherapeutic agent ͉ experimental gene therapy ͉ E-cadherin S omatostatin is a widely distributed peptide that negatively regulates a number of cellular processes, including growth of multiple epithelial cell types (1). Somatostatin and its stable analog suppress the growth of various cancer cells, including neuroendocrine tumors that express somatostatin receptors (2, 3). The evidence indicates that direct antiproliferative effects of somatostatin and its analogs are mediated by specific cell surface receptors. Five subtypes of somatostatin receptors have been cloned from human, mouse, and rat (4). We found that, among them, the subtypes sst1, sst2, and sst5 mediate the antiproliferative effect of stable somatostatin analogues in vitro (5). We demonstrated that somatostatin subtype 2 (sst2) receptor mediated this antiproliferative effect through the association and stimulation of the tyrosine phosphatase src homology 2-containing tyrosine phosphatase 1 (SHP-1) activity (5, 6) and the subsequent arrest of cells in G 0 ͞G 1 phase of cell cycle in response to an up-regulation of CDKI p27 KIP1 expression and an increase in hypopho...

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confidence: 99%

Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238

Benali

Cordelier

Calise

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

101

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“…A utilização de derivados da somatostatina tem tido destacada importância no tratamento clínico do tumor carcinóide, pelo controle da sintomatologia de síndrome carcinóide 53,54 e, inclusive, indução de apoptose e de regressão tumoral quando utilizados em alta dosagem 55 . Os derivados mais utilizados atualmente têm sido o octreotide, doses de 0,05 a 0,5 mg SC três vezes ao dia 56 , e o lanreotide, 1 mg 57 ou 5 mg 58 SC três vezes ao dia. São inconvenientes a freqüên-cia das administrações injetáveis, as reações observadas nos locais de aplicação e o custo do tratamento para os pacientes.…”

Section: Tratamento Coadjuvanteunclassified

Diagnóstico e tratamento de tumores carcinóides do trato digestivo

Fernandes¹,

Pucca²,

Matos³

2002

Rev. Assoc. Med. Bras.

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RESUMO Os autores verificam as características dos tumores carcinóides de acordo com sua localização no trato digestivo. Apesar de sua baixa velocidade de crescimento e de metastatização, tais neoplasias são malignas e devem ser submetidas a ressecção cirúrgica. Casos avançados com metástases são tratados com derivados da somatostatina, com paliação dos sintomas, ocasional regressão das lesões e obtenção de maior sobrevida. Lesões apendiculares e retais têm melhor prognóstico, talvez pelo diagnóstico precoce efetuado.UNITERMOS: Tumor carcinóide. Neoplasias gastrintestinais. Tumores neuroendócrinos. Neoplasias do sistema digestivo. INTRODUÇÃOOs tumores carcinóides são neoplasias do sistema celular neuroendócrino difuso. O termo tumor neuroendócrino tem sido proposto para a referida entidade 1,2,3,4 . É certo o envolvimento de fatores genéticos na etiologia. É provável que a deleção do gen supressor PLCβ3 provoque descontrole de crescimento de células neuro-endócrinas, com distorção do processo de apoptose 5,6 e desenvolvimento de neoplasias.A incidência de tumores carcinóides oscila em 0,7 casos por 100.000 habitantes 7,8 . A incidência real deve ser maior, considerando-se um achado mais freqüente observado em necrópsias 9 . Certo número de lesões incipientes não deve ultrapassar estágios iniciais no decorrer da existência.Os doentes têm média etária de 50 anos quando se efetua o diagnóstico da neoplasia 7,10 . As mais freqüentes sedes de tumores carcinóides são o trato gastrintestinal (73,7%) e o sistema r e s p i r a t ó r i o (25,1%). No aparelho digestivo, os principais órgãos afetados são intestino delgado, apêndice cecal e reto (Tabela I). Têm ocorrido mais diagnósticos em virtude de um melhor conhecimento do processo neoplásico e dos aperfeiçoa-mentos obtidos nos métodos de investigação disponíveis; contudo, aparentemente, a incidência tem se elevado nas últimas duas décadas 11. Classificação e fisiopatologiaOs tumores carcinóides têm sido classificados de acordo com sua formação embriológica, se originários do intestino anterior, médio ou posterior 12 .Os tumores de origem embrionária no intestino anterior acometem, na fase adulta, o trato respiratório e o timo. Os originários no intestino médio são os de maior freqüên-cia, manifestando-se em jejuno, íleo e cólon direito e sendo os maiores produtores de serotonina. Lesões inerentes ao intestino posterior embrionário acometem o cólon esquerdo e o reto na fase adulta 9

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“…The effect could be a direct one on the tumor tissue itself, it could be related to hormone production as somatostatin analogues Peptide receptor scintigraphy with the radiolabeled somatostatin analogue [ 111 In-DTPA-D-Phe]octreotide can suppress hormone secretion, and/or it could be associated with tumor growth [7,8]. However, as somatostatin has become a standard procedure for localizing GEP tumors.…”

Section: Value Of Somatostatin Receptor Scintigraphy For Tumor Localimentioning

confidence: 99%

“…available evidence, scintigraphy is an important imaging modality in patients with GEP tumors (examples are Tumor growth varies from one patient to another with some tumors and their metastases remaining unchanged given in figure 1a, 1b). It allows imaging of all body areas with high sensitivity and specificity, and has equal or for months or years, while other tumors show explosive growth [8]. In general, however, GEP endocrine tumors greater sensitivity to other imaging procedures.…”

Section: Value Of Somatostatin Receptor Scintigraphy For Tumor Localimentioning

confidence: 99%

The Role of Octreotide in the Treatment of Gastroenteropancreatic Endocrine Tumors

Degen

Beglinger²

1999

Digestion

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Gastrointestinal-endocrine pancreatic (GEP) tumors are rare, occurring in less than 1% of the population. They are usually divided into functionally active or nonfunctioning tumors. Functionally active tumors produce a variety of substances (mainly peptides or serotonin). The tumors are classified according to the dominant clinical syndrome that they cause. Surgery is the treatment of choice in patients with GEP tumors and it should always be considered, even if total tumor excision cannot be achieved. Reduction in tumor mass (debulking) may improve the patients symptoms. Medical treatment is used in patients with advanced malignant endocrine tumors. The most important compounds to control symptoms in these patients are somatostatin analogues. Natural somatostatin is produced in different molecular forms and has inhibitory effects on a number of functions. The observation of potent inhibitory effects on various hormone-secreting cells led to the use of somatostatin for symptomatic treatment of peptide-secreting tumors. Natural somatostatin is not suitable for long-term clinical application; therefore, synthetic somatostatin analogues were developed with improved pharmacokinetic characteristics. The best characterized analogue, octreotide, has been successfully applied to patients with functioning GEP tumors. Octreotide can dramatically ameliorate the debilitating symptoms of patients suffering from the clinical manifestations of endocrine tumors such as diarrhea and flushing. The success of octreotide therapy is best reflected in terms of its impact on the patient''s quality of life as defined by the activity to perform normal daily activities.

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Control of Growth in Neuroendocrine Gastro-Enteropancreatic Tumours

Cited by 12 publications

References 7 publications

Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238

Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238

Diagnóstico e tratamento de tumores carcinóides do trato digestivo

The Role of Octreotide in the Treatment of Gastroenteropancreatic Endocrine Tumors

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