ISSN:0012-2823    

DOI:10.1159/000201381

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

With the technique of in vivo somatostatin (SRIF) receptor (sst) scintigraphy a variety of human sst-positive tumours can be visualised 24-48 h after intravenous injection of the radiolabelled (SRIF) analogue [111In-DTPA-D-Phe1ctreotide. This rather long residence time of radioactivity on tumours suggests that the radioligand is internalised by the tumour cells; literature data for normal pituitary and pancreatic islet cells agree with this. Internalised SRIF has been found to be associated with cytoplasmic organelles, especially the Golgi apparatus, lysosomes and secretory granules. We have found that mouse AtT20 and primary cultures of human growth-hormone-secreting pituitary adenoma cells internalised a high amount of radio-iodinated [Tyr3]octreotide. Since octreotide binds with high affinity to the sst5 and ssts subtypes and because both sst subtypes are expressed in these cells, one or both subtypes may be involved in this process. We also found that unlabelled octreotide, SRIF-14 or SRIF-28 can increase the intemalisation of the radioligand. These observations, together with other studies on the manipulation of sst expression, may help to optimise the uptake of radioligand in in vivo sst scintigraphy in humans and improve the potential effect of radiotherapy with radiolabelled (subtype-specific) SRIF analogues.

ISSN:0012-2823    

DOI:10.1159/000201382

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The expression of somatostatin receptors (ssts) on human tumours is the basis for the successful therapeutic and diagnostic application of (radiolabelled) somatostatin analogues. Manipulation (up-regulation) of sst expression might improve the uptake of radioligand in in vivo scintigraphy of human sst-positive tumours, as well as the potential success of radiotherapy using radiolabelled SRIF analogues. In clonal pituitary cell lines, agonist exposure (SRIF-14, SRIF-28, octreotide) has been shown to either reduce or increase sst (subtype) expression, suggesting cell-type-specific responsiveness. In addition, glucocorticoids and oestrogens were shown to down- and up-regulate, respectively, sst numbers. So far, little information is available with respect to sst (subtype) regulation in non-pituitary-derived cell types. We have found that sst expression in the model of the transplantable prolactin (PRL)-secreting rat pituitary tumour 7315b is mainly dependent upon the presence of oestradiol (E2), both in vivo and in vitro. This tumour is sst negative in vivo. In vitro, the addition of E2 induces sst expression (sst2 and sst3 subtypes). The in vivo administration of E2 (20 μg/day subcutaneously) to 7315b-tumour-bearing rats induces sst2 mRNA expression. The absence of sst expression in 7315b tumours in vivo may be due to the inhibition of ovarian E2 production by the high circulating PRL levels in the 7315b-prolactinoma-bearing rats. Indeed, no detectable E2 levels were found in the serum of 7315b-tumour-bearing rats. Taken together, our data suggest that the 7315b rat prolactinoma can indirectly manipulate (down-regulate) its own sst expression, in vivo, via its host. This experimental 7315b prolactinoma model might be representative for most untreated female prolactinoma patients. Clinically, patients with microprolactinomas do not benefit from octreotide treatment

ISSN:0012-2823    

DOI:10.1159/000201383

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Gastric carcinoids are the sequel of enterochromaffin-like (ECL) cell hyperplasia, and are usually associated with a low-acid state and hypergastrinaemia. The somatostatin (SRIF) analogue octreotide has been noted to decrease both plasma gastrin levels and ECL cell hyperplasia/neoplasia in human and rodent experimental models. The African rodent, mastomys, exhibits a genetic propensity to gastric carcinoid formation which can be significantly accelerated by acid-inhibition-induced hypergastrinaemia. Thus a low-acid state induced by either irreversible H2 blockade or proton pump inhibition shortens the natural 2-year induction time to 4 months. In vivo studies of this model demonstrate that, similar to the human situation, octreotide decreases plasma gastrin levels and inhibits low-acid-induced gastric carcinoid formation. In vitro, using isolated ECL cells, SRIF inhibits both gastrin-stimulated ECL cell histamine secretion and DNA synthesis. This mechanism appears to function via the SRIF receptor (SSTR) subtype 2, which we have identified in both naive and transformed ECL cells. Thus the direct effect of SRIF regulation of ECL cell function is mediated by at least a SSTR2 subtype. It is possible that the alteration of the SSTR2 during ECL cell transformation may contribute to the genetic susceptibility of the mastomys to carcinoid tumour formation. The precise anti-proliferative mechanism of SRIF and its role in neuroendocrine cell transformation remain to be defined. Pharmacological manipulation of the SSTR2 may provide a viable therapeutic and diagnostic target in the management not only of ECL cell neoplasia but also other types of neuroendocrine cell tumour.

ISSN:0012-2823    

DOI:10.1159/000201385

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

We consider the multiple interacting factors which lead to the proliferation of human gastric enterochromaffin-like (ECL) cells, and control of this proliferation by somatostatin and its analogues. Somatostatin receptors occur in human fundic mucosa, and octreotide can be considered a useful therapeutic tool to control gastrin-driven ECL cell growth in humans.

ISSN:0012-2823    

DOI:10.1159/000201386

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Uptake of α-methyl-D-glucoside, a nonmetabolizable glucose analogue, by everted intestinal sleeves was studied in virgin, pregnant and lactating rats. The animals showed an increase in jejunal and ileal tissue mass, mucosal mass, nominal surface area, and enzymatic activities. No changes were observed in the carrier affinity throughout the breeding stages. Nevertheless there was a significant increase in glucose carrier density (Vmax) per unit of length of jejunum and ileum in pregnant and lactating animals. Integrating the results obtained, an increased overall ability to transport hexoses by nonspecific adaptation can be observed in breeding stages

ISSN:0012-2823    

DOI:10.1159/000201307

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The aim of the present study was to selectively target a β-emitter-labelled octreotide analogue to somatostatin (SRIF)-receptor-expressing tumours and to evaluate the feasibility of SRIF-receptor-mediated radiotherapy by delivering a lethal dose of radiation to the tumour. The most promising compound in a series of DTPA-coupled octreotide analogues was DTPA-benzyl-acetamido-D-Phe1, Tyr3ctreotide (SDZ413). In vitro, SDZ413 binds with nanomolar affinity to SRIF-receptors (IC50 = 4.0 nM) and inhibits growth hormone release from primary cultures of rat pituitary cells with an IC50 of 7.2 nM. Biodistribution studies with [90Y]SDZ413 demonstrated a fast and significant SRIF-receptor-specific accumulation of the labelled conjugate (tumour/muscle ratio after 24 h: 52/1). [90Y]SDZ413 was effective in the radiotherapy of SRIF-receptor-positive tumours in a nude mouse model. A single treatment with [90Y]SDZ413 led to a significant decrease (25%) of tumour mass. This effect was mediated by the intact radioligand, since treatment with [90Y]SDZ978, a derivative of SDZ413 which does not bind with high affinity to SRIF-receptors or with the unlabelled SDZ413 alone, failed to affect tumour growth. These results suggest that receptor-targeted radiotherapy with a 90Y-labelled octreotide analogue represents a new strategy for the treatment of SRIF-receptor-positive tumours that have been previously diagnosed with OctreoScan®111 (pentetreotide

ISSN:0012-2823    

DOI:10.1159/000201387

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The somatostatin analogue octreotide (SMS 201-995) exerts potent anti-proliferative effects in a number of experimental cancer models. Here we report on the inhibitory effect of octreotide in combination with the chemothera-peutic agents mitomycin C, doxorubicin, 5-fluorouracil, or taxol on the growth of AR42J pancreatic cancer cells in vitro. The dose-dependent anti-proliferative effects of mitomycin C, doxorubicin and taxol were synergistically enhanced by octreotide. Combinations of octreotide and 5-fluorouracil resulted either in additive or, at high concentrations of the chemotherapeutic agent, in synergistic interactions. Combined treatment with doxorubicin and octreotide was also studied for time dependency and potential efficacy in tumour-bearing animals. Pretreatment (24 h) with doxorubicin resulted in clear synergy. However, pretreatment with octreotide 24 h prior to addition of doxorubicin resulted only in an additive interaction. It was shown in AR42J-tumour-bearing nude mice that the combination of doxorubicin and octreotide was well tolerated. Tumour growth was inhibited to 9% of controls, compared with 44% in the doxorubicin alone arm (day 14 of treatment). Our in vitro and in vivo interaction studies suggest that octreotide potentiates the effect of various chemotherapeutic agents in a synergistic or additive manner.

ISSN:0012-2823    

DOI:10.1159/000201388

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Tamoxifen is useful in the treatment of breast cancer, but its effects in metastatic disease are rarely long term, and development of resistance to the drug is common. In vitro and in vivo data demonstrate anti-neoplastic (anti-proliferative) effects of somatostatin analogues, which may occur via binding to somatostatin receptors on the neoplastic cells, and/or via reductions in insulinlike growth factor-1 bioactivity. Moreover, several lines of evidence from in vitro and in vivo studies indicate that the long-acting somatostatin analogue octreotide enhances the anti-neoplastic effects of anti-oestrogenic agents such as tamoxifen. The anti-oestrogen-somatostatin approach appears to have a favourable long-term toxicity profile. Large-scale clinical trials are currently being planned to investigate the efficacy of combined tamoxifen plus octreotide therapy compared to tamoxifen alone in patients with breast cancer.

ISSN:0012-2823    

DOI:10.1159/000201389

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

We have developed a 14C-urea breath test to follow the course of Helicobacter felis infection in mice. Peak 14CO2 production occurred approximately 8 min after substrate administration. The test values were compared to those from a rapid urease test and correlated with the presence of pathogens by histology. The sensitivity was 99%, specificity 91%, positive predictive value 95% and negative predictive value 99% when the assay was conducted in fasted mice. We conclude that in mice the breath test analysis is a useful noninvasive method for detecting the presence of H. felis or for evaluating therapeutic agents affecting growth or survival of the organism.

ISSN:0012-2823    

DOI:10.1159/000201309

出版商:S. Karger AG    

年代:1996

数据来源: Karger