Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To create cytotoxic hybrid analogs of somatostatin (SST), octapeptides RC-160 (D-Phe-Cys-Tyr-D-Trp- Lys-Val-Cys-Trp-NH2) and RC-121 (D-Phe-Cys-Tyr-D-Trp- Lys-Val-Cys-Thr-NH2) were linked to doxorubicin (DOX) or its superactive derivative, 2-pyrrolino-DOX (AN-201). The conjugation was performed by coupling N-9-fluorenylmethoxycarbonyl (N-Fmoc)-DOX-14-O-hemiglutarate or 2-pyrrolino-DOX-14-O-hemiglutarate to the amino terminus of [Lys(Fmoc)5]RC-160 yielding AN-163 and AN-258, respectively, after deprotection. The respective cytotoxic conjugates of RC-121 (AN-162 and AN-238) were prepared similarly. In vitro tests on human cancer cell lines-MKN-45 gastric cancer, MDA-MB-231 breast cancer, PC-3 prostate cancer, and MIA PaCa-2 pancreatic cancer-demonstrated that the antiproliferative activity of the cytotoxic radicals in these conjugates was virtually retained. In H-345 human small cell lung carcinoma cell line, conjugates of RC-121 preserved the cytotoxic activity of their radicals, but the hybrids with RC-160 showed approximately 10 times lower activity. The ability of the carriers and the hybrids to inhibit the binding of 125I-labeled RC-160 to receptors for SST on rat pituitary membrane preparation was also determined. The cytotoxic conjugates inhibited 50% of the specific binding of the radioligand in the nanomolar concentration range (IC50 < 80 nM). When SST-like activities of AN-238 and its carrier, RC-121, were compared in the rat pituitary superfusion system, both compounds were found to suppress a stimulated growth hormone release at nanomolar concentrations. Preliminary studies in animal models of breast and prostate cancers showed that AN-238 is less toxic than AN-201 and more potent in inhibiting tumor growth. These highly active cytotoxic analogs of SST have been designed as targeted antitumor agents for the treatment of various cancers expressing receptors for SST octapeptides.
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PMID:Synthesis and biological evaluation of cytotoxic analogs of somatostatin containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin. 946 96

Several authors proposed the stage at diagnosis and some histopathological features as prognostic factors of bronchial carcinoids. However, since large tumour diameters or nodal metastases are frequently associated to aggressive histology, their prognostic role is unclear. To investigate the relationships between the clinicopathological parameters at diagnosis and outcome, 21 patients were analysed. Overall 26% of the radically resected patients recurred. Recurrences and disease-specific mortality were related to atypical histology and, only in cases with typical histology, to the presence of hilar or mediastinal lymph node metastases. These prognostic factors were valuable independently of the size of the primary tumour, that was remarkably homogeneous, always less than 3 cm, thus not predictive of recurrence. Moreover we evaluated the role of somatostatin receptor scintigraphy, a diagnostic tool only preliminary studied in this field. Scintigraphy with 111In-octreotide revealed the primary tumours at diagnosis (8/8), the increase in tumour size in two unresected patients, and all the cases of recurrent or metastatic disease (5/11), sometimes before the appearance of symptoms. These results suggest the usefulness of histology and nodal status as prognostic factors in clinical practice. Somatostatin receptor scintigraphy turns out to be a powerful diagnostic tool, for an accurate staging and an early diagnosis of recurrence in bronchial carcinoids.
Lung Cancer 1998 Nov
PMID:Bronchial carcinoid tumours: a study on clinicopathological features and role of octreotide scintigraphy. 1002 17

In view of non-specific toxicity of most chemotherapeutic agents against normal cells, the development of targeted chemotherapy is warranted. Efficient targeting of chemotherapeutic drugs to the cancerous area could be of great benefit for patients with advanced or metastatic tumors. Targeted cytotoxic peptide conjugates are hybrid molecules composed of a peptide carrier which binds to receptors on tumors and a cytotoxic moiety. New cytotoxic analogs of LHRH, AN-152 in which doxorubicin (DOX) is linked to [d-Lys(6)]LHRH, and AN-207 which consists of 2-pyrrolino-DOX (AN-201) coupled to the same carrier, show high-affinity binding and are much less toxic and more effective in vivo than their respective radicals in inhibiting tumor growth in LHRH receptor-positive models of human ovarian, mammary, or prostatic cancer. These results suggest that targeted cytotoxic LHRH analogs such as AN-207 could be considered for treatment of these cancers. The presence of receptors for bombesin-like peptides on a wide variety of tumors prompted us to use some of our bombesin/gastrin-releasing peptide antagonists as carrier molecules. Cytotoxic bombesin analogs, such as AN-215 containing AN-201, might find application in the treatment of small cell lung carcinoma (SCLC), and colorectal, gastric, pancreatic, mammary, and prostatic cancers. Since somatostatin receptors are found in various human neoplasms and the receptor subtypes to which octapeptide analogs bind with high affinity have been identified, we synthesized several cytotoxic somatostatin analogs including AN-162 and AN-238 containing DOX and 2-pyrrolino-DOX respectively, linked to octapeptide RC-121. Cytotoxic somatostatin analog AN-238 efficaciously inhibits growth of human breast or prostate cancers expressing somatostatin receptors-2 and -5 and can be used for receptor-targeted chemotherapy. Cytotoxic somatostatin analogs might also find applications for the therapy of human pancreatic, colorectal, and gastric cancer as well as brain tumors and non-SCLC. Cytotoxic compounds linked to analogs of hormonal peptides like LHRH, bombesin, and somatostatin that can be targeted to certain tumors possessing receptors for those peptides could be an important addition to oncological armamentarium.
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PMID:Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors. 1040 15

Somatostatin (SS) and SS analogues inhibit the growth of various kinds of endocrine and exocrine cells via the SS receptor (SSTR). Carcinoid tumor is representative of the tumors treatable by SS analogues. We examined the expression of SSTR2A by immunohistochemical and in situ hybridization methods with a specific antibody against a synthesized 20-amino acid peptide of the COOH terminus of human SSTR2A and oligonucleotide probes in 62 endocrine tumors of various kinds: pancreatic endocrine tumor; carcinoid; neuroendocrine carcinoma; medullary thyroid carcinoma; pheochromocytoma; and small cell carcinoma of the lung, neuroblastoma, and ganglioneuroma. SSTR2A was expressed in 87% of these tumors and at both primary and metastatic sites. The immunohistochemical reactivity of SSTR2A was strong on the cell membrane and less intense in the cytoplasm of the tumor cells. SSTR2A mRNA was also detected in the tumor cells. The results indicate the usefulness of SSTR2A analogues for the treatment of neuroendocrine tumors, even metastatic ones: metastatic carcinoids, metastatic pheochromocytomas, tumors that adhered to large vessels, and neuroendocrine carcinomas.
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PMID:Immunohistochemical expression of somatostatin type 2A receptor in neuroendocrine tumors. 1058 62

Although human small cell lung carcinoma (SCLC) cell lines are typically anchorage-independent and do not attach on most extracellular matrix proteins, OH-1, and several other SCLC cell lines attached on substrates coated with thrombospondin-1 (TSP1). SCLC cells grew long-term as adherent cells on a TSP1-coated substrate. Adhesion of SCLC cells on TSP1 was inhibited by heparin, function-blocking antibodies recognizing alpha3 or beta1 integrin subunits, and by soluble alpha3beta1 integrin ligands. SCLC cells extended neurite-like processes on a TSP1 substrate, which was also mediated by alpha3beta1 integrin. Process formation on a TSP1 substrate was specifically stimulated by epidermal growth factor and somatostatin. Adhesion on TSP1 weakly inhibited SCLC cell proliferation, but this inhibition was strongly enhanced in the presence of epidermal growth factor. TSP1 and an alpha3beta1 integrin-binding peptide from TSP1 also inhibited proliferation when added in solution. High-affinity binding of 125I-labeled TSP1 to OH-1 cells was heparin-dependent and may be mediated by sulfated glycolipids, which are the major sulfated glycoconjugates synthesized by these cells. Synthesis or secretion of TSP1 by SCLC cells could not be detected. On the basis of these results, the alpha3beta1 integrin and sulfated glycolipids cooperate to mediate adhesion of SCLC cells on TSP1. Interaction with TSP1 through this integrin inhibits growth and induces neurotypic differentiation, which suggests that this response to TSP1 may be exploited to inhibit the progression of SCLC.
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PMID:Thrombospondin-1 promotes alpha3beta1 integrin-mediated adhesion and neurite-like outgrowth and inhibits proliferation of small cell lung carcinoma cells. 1066 1

Somatostatin receptors type 2 (sst2) have been frequently detected in neuroendocrine tumors and bind somatostatin analogues, such as octreotide, with high affinity. Receptor autoradiography, specific mRNA detection and, more recently, antisst2 polyclonal antibodies are currently employed to reveal sst2. The aim of the present study was to investigate by three different techniques the presence of sst2 in a series of 26 neuroendocrine tumors of the lung in which fresh frozen tissue and paraffin sections were available. It was possible, therefore, to compare, in individual cases, RNA analysis studied by reverse transcriptase polymerase chain reaction (RT-PCR), in situ hybridization (ISH), and immunohistochemistry. A series of 20 nonneuroendocrine lung carcinoma samples served as controls. RT-PCR was positive for sst2 in 22 of 26 samples, including 15 of 15 typical carcinoids, 5 of 6 atypical carcinoids, and 2 of 5 small-cell carcinomas. The sst2 mRNA signal obtained by RT-PCR was strong in the majority (87%) of typical carcinoids and of variable intensity in atypical carcinoids and small-cell carcinomas. A weakly positive signal was observed in 5 of 20 control samples. In immunohistochemistry, two different antibodies (anti-sst2) were employed, including a monoclonal antibody, generated in the Department of Pathology, University of Turin. In the majority of samples a good correlation between sst2 mRNA (as detected by RT-PCR) and sst2 protein expression (as detected by immunohistochemistry) was observed. However, one atypical carcinoid and one small-cell carcinoma had focal immunostaining but no RT-PCR signal. ISH performed in selected samples paralleled the results obtained with the other techniques. A low sst2 expression was associated with high grade neuroendocrine tumors and with aggressive behavior. It is concluded that 1) neuroendocrine tumors of the lung express sst2, and there is a correlation between the mRNA amount and the degree of differentiation; 2) immunohistochemistry and ISH are reliable tools to demonstrate sst2 in these tumors; and 3) sst2 identification in tissue sections may provide information on the diagnostic or therapeutic usefulness of somatostatin analogues in individual patients with neuroendocrine tumors.
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PMID:Correlative immunohistochemical and reverse transcriptase polymerase chain reaction analysis of somatostatin receptor type 2 in neuroendocrine tumors of the lung. 1071 13

The effects of prostaglandin E2 (PGE2) and vasoactive intestinal peptide (VIP) on vascular endothelial cell growth factor (VEGF) mRNAs were investigated using lung cancer cells. By RT-PCR, VEGF(121), VEGF(165), and VEGF(189), but not VEGF(206) isoforms were detected in all lung cancer cell lines and biopsy specimens examined. By Northern blot, VEGF mRNA was detected in all small cell lung cancer (SCLC) and non-SCLC (NSCLC) cell lines examined. PGE2, VIP and forskolin caused increased VEGF expression in a time- and concentration-dependent manner using NSCLC cell line NCI-H157. Approximately 1 microM PGE2, 0.1 microM VIP and 50 microM forskolin caused cAMP elevation, 64-, 33- and 128-fold, respectively, using NCI-H157 cells after 5 min. The increase in cAMP caused by PGE(2) and VIP was reversed by somatostatin (SST). Also 1 microM PGE2, 0.1 microM VIP and 50 microM forskolin increased the VEGF mRNA 2.0-, 1.5- and 2.3-fold, respectively, after 4 h. The increase in VEGF mRNA caused by PGE2, VIP and forskolin was inhibited by H-89, a protein kinase A inhibitor. A VIP receptor antagonist, VIPhybrid, inhibited the increase in cAMP and VEGF mRNA caused by VIP. By ELISA, VEGF was detected in the conditioned media exposed to the lung cancer cell lines. These results suggest that VEGF synthesis in and secretion from lung cancer cells can be regulated by agents, which cause adenylyl cyclase activation.
Lung Cancer
PMID:Prostaglandin E2 and vasoactive intestinal peptide increase vascular endothelial cell growth factor mRNAs in lung cancer cells. 1116 99

Recently, we developed a cytotoxic analogue of somatostatin (SST), AN-238, in which the SST carrier peptide RC-121 was linked to 2-pyrrolinodoxorubicin (2-pyrrolino-DOX) (AN-201), a potent derivative of doxorubicin. AN-238 can be targeted to SST receptors (SSTRs) on tumours. In the present study, we evaluated the effects of AN-238 on the growth of H-69 small-cell lung carcinoma (SCLC) and H-157 non-SCLC xenografted into nude mice. High affinity binding sites for SST are present in H-69 SCLC and were now detected in H-157 non-SCLC xenografts, but not in H-157 cells. A strong expression of the human SSTR subtype 2 (hSSTR-2) and a weaker expression of subtype 5 (hSSTR-5) was found in H-69 SCLC cells, but not in H-157 non-SCLC cells. However, a strong expression of mRNA for mouse (m)SSTR-2 could be detected in H-157 xenografts. AN-238 effectively inhibited the growth of H-69 SCLC tumours in nude mice. Twenty-six days after a single injection of AN-238 at 200 nmol/kg, the volume of H-69 tumours was decreased by approximately 55% (P<0.05) compared with the controls, while AN-201 at the same dose was highly toxic and produced only a minor tumour inhibition. To evaluate the potency of multiple doses of AN-238, nude mice bearing H-69 SCLC received three injections of AN-238 at 150 nmol/kg on days 1, 12 and 28. In the period of 42 days after the first injection, the growth rate of H-69 tumours was approximately 50% lower than that of controls. In nude mice bearing H-157 non-SCLC tumours, a single i.v. administration of AN-238 at 200 nmol/kg inhibited tumour volume by 91% after 28 days (P<0.01 compared with controls). AN-201 was toxic and ineffective at the same dose. Two injections of AN-238 at 150 nmol/kg given on days 1 and 18 produced 83% inhibition of H-157 tumour growth (P<0.01 versus controls). AN-238 given as a single dose of 200 nmol/kg induced necrosis, while two injections of 150 nmol/kg induced apoptosis in the tumour tissue. Our results indicate that targeted cytotoxic SST analogue AN-238 could be considered for therapy of both SCLC and non-SCLC.
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PMID:A targeted cytotoxic somatostatin (SST) analogue, AN-238, inhibits the growth of H-69 small-cell lung carcinoma (SCLC) and H-157 non-SCLC in nude mice. 1129 Apr 38

Radiolabelled somatostatin analogues have been used in diagnostic and therapeutic nuclear medicine to treat cancerous tumours. Lanreotide, a cyclic octapeptide, beta-naphthyl-peptide, with antiproliferative action on human small cell lung carcinoma was (188)Re labelled and characterised, and its biodistribution was studied in mice. Molecular modelling indicates that the lipophilic radiopharmaceutical might be an oxo-rhenium (V) penta-coordinated complex. The implanted human cervical tumour of epidermoid origin was positive for cytokeratins and Vimentin. Uptake of (188)Re-labelled peptide in the implanted tumour in athymic mice was 6.2+/-2.9% and was rapidly cleared via the hepatobiliary system. (188)Re-beta-naphthyl-peptide might be a potential therapeutic agent.
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PMID:Uptake of (188)Re-beta-naphthyl-peptide in cervical carcinoma tumours in athymic mice. 1132 44

The development of targeted cytotoxic analogs of hypothalamic peptides for the therapy of various cancers is reviewed and various oncological studies on experimental tumors are summarized. Novel therapeutic modalities for breast, prostate and ovarian cancer consist of the use of targeted cytotoxic analogs of LH-RH containing doxorubicin (DOX) or 2-pyrrolino-DOX. The same radicals have been incorporated into cytotoxic analogs of somatostatin which can be also targeted to receptors for this peptide in prostatic, mammary, ovarian, renal and lung cancers, brain tumors and their metastases. A targeted cytotoxic analog of bombesin containing 2-pyrrolino-DOX has also been synthesized and successfully tried in experimental models of prostate cancer, small cell lung carcinoma and brain tumors. The development of these new classes of peptide analogs should lead to a more effective treatment for various cancers.
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PMID:New approaches to treatment of various cancers based on cytotoxic analogs of LHRH, somatostatin and bombesin. 1263 97


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