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Biopolymers 2002Since the discovery of somatostatin (sst) in 1973, numerous chemical and biological studies have been carried out to develop sst analogs with enhanced resistance to... (Review)
Review
Since the discovery of somatostatin (sst) in 1973, numerous chemical and biological studies have been carried out to develop sst analogs with enhanced resistance to proteases and prolonged activity. Three highly potent sst analogs-octreotide, lanreotide, and vapreotide-are now available in the clinic, and demonstrate efficacy in the treatment of tumors of the pituitary and the gastroenteropancreatic tract. The most striking effect is the control of hormone hypersecretion associated with these tumors. Available data on growth suppression in patients indicate a limited antiproliferative action, tumor shrinkage is observed in 10-20% patients, and tumor stabilization in about half of the patients for duration of 8-16 months. Eventually, however, all patients escape from sst analog therapy with regard to both hormone hypersecretion and tumor growth, the only exception being observed in acromegalic patients who do not experience tachyphylaxis even after more than 10 years of daily octreotide injection. The mechanism underlying the escape phenomenon is not yet clarified. Regarding the molecular mechanisms involved in sst antineoplastic activity, both indirect and direct effects via specific somatostatin receptors (SSTRs) expressed in the target cells have be described. Direct action may result from blockade of mitogenic growth signal or induction of apoptosis following interaction with SSTRs. Indirect effects may be the result of reduced or inhibited secretion of growth-promoting hormones and growth factors that stimulate the growth of various types of cancer; also, inhibition of angiogenesis or influence on the immune system are important factors. Five SSTR subtypes have been identified so far, which are variably expressed in a variety of tumors such as gastroenteropancreatic (GEP) tumors, pituitary tumors, and carcinoid tumors. Although all five SSTR subtypes are linked to adenylate cyclase, they are now known to affect multiple other cellular signaling systems and hence they differentially participate in the regulation of the various cellular processes. The finding of several laboratories that SSTR-expressing tumors frequently contain two or more SSTR subtypes, and the recent discovery that SSTR subtypes might form homo/heterodimers to create a novel receptor with different functional characteristics, expand the array of selective SSTR activation pathways and subsequent intracellular signaling cascades. This may lead to improved clinical protocols that take into account possible synergistic interactions between the SSTR subtypes present on the same cancer cell. Radiolabeled sst analogs, such as [(111)In]-[diethylenetriamine pentaacetic acid (DTPA)-D-Phe(1)]-octreotide (OcreoScan), have proved to be very useful for tumor scintigraphy and internal radiotherapy of SSTR overexpressing tumors. The recent introduction of the metal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) considerably improved the stability of the radioconjugates, making possible the incorporation of a variety of radionuclides, such as (90)Y for receptor-mediated radionuclide therapy or (68)Ga for positron emission tomography (PET). Another promising area is the development of sst conjugates incorporating cytotoxic anticancer drugs.
Topics: Amino Acid Sequence; Gene Expression; Humans; Molecular Sequence Data; Neoplasms; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin
PubMed: 12385036
DOI: 10.1002/bip.10256 -
The Prostate Aug 2002Antagonists of growth hormone-releasing hormone (GHRH) such as JV-1-38 can inhibit androgen-independent prostate cancer directly by several mechanisms and/or indirectly...
Inhibition of proliferation of PC-3 human prostate cancer by antagonists of growth hormone-releasing hormone: lack of correlation with the levels of serum IGF-I and expression of tumoral IGF-II and vascular endothelial growth factor.
BACKGROUND
Antagonists of growth hormone-releasing hormone (GHRH) such as JV-1-38 can inhibit androgen-independent prostate cancer directly by several mechanisms and/or indirectly by suppressing growth hormone/insulin-like growth factor-I (GH/IGF-I) axis. To shed more light on the mechanisms involved, the effects of JV-1-38 on PC-3 human prostate cancer were compared with those of somatostatin analog RC-160 in vivo and in vitro.
METHODS
Nude mice bearing PC-3 tumors received JV-1-38 (20 microg), RC-160 (50 microg) or a combination of JV-1-38 and RC-160. The concentration of IGF-I in serum and the expression of mRNA for IGF-II and vascular endothelial growth factor (VEGF) in tumor tissue were investigated.
RESULTS
In vivo, the final volume of PC-3 tumors treated with JV-1-38 was significantly lowered by 49% (P < 0.01), whereas RC-160 exerted only 30% inhibition (NS), compared with controls. Combined use of both compounds augmented tumor inhibition to 63% (P < 0.001). Serum IGF-I levels were decreased only in mice treated with RC-160. JV-1-38 suppressed mRNA for IGF-II in PC-3 tumors by 42%, whereas RC-160 alone or in combination with JV-1-38 caused a 65% reduction. JV-1-38 and RC-160 used as single drugs decreased the expression of VEGF by 50%, and their combination caused a 63% reduction. In vitro, JV-1-38 inhibited the proliferation of PC-3 cells by 39%. This effect could be partially reversed by addition of IGF-I to the serum-free medium. RC-160 alone did not affect the PC-3 cell growth in vitro, but in combination with JV-1-38 it augmented the antiproliferative effect of the GH-RH antagonist to 72%. Exposure to JV-1-38 in vitro reduced the expression of mRNA for IGF-II in PC-3 cells by 55% but did not change VEGF mRNA levels, whereas RC-160 had no effect.
CONCLUSIONS
The antiproliferative effect of JV-1-38 was not associated with the suppression of serum IGF-I and was only partially correlated with the expression of IGF-II and VEGF in PC-3 tumors, suggesting that other mechanisms play a role in the antitumor action of GHRH antagonists. Nevertheless, the stronger inhibition of tumor growth after combined treatment with JV-1-38 and RC-160 indicates that the interference with multiple local stimulatory factors leads to an enhanced inhibition of prostate cancer.
Topics: Animals; Antineoplastic Agents; Cell Division; Drug Combinations; Endothelial Growth Factors; Growth Hormone-Releasing Hormone; Humans; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Lymphokines; Male; Mice; Mice, Nude; Prostatic Neoplasms; RNA, Messenger; Somatostatin; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 12111694
DOI: 10.1002/pros.10105 -
Journal of Hepatology Jul 2002
PubMed: 12076882
DOI: 10.1016/s0168-8278(02)00170-8 -
Annals of Oncology : Official Journal... May 2002Somatostatin (SST) analogues represent a novel approach for the treatment of certain cancers. The objective of this article is to summarise the current knowledge on SST... (Review)
Review
BACKGROUND
Somatostatin (SST) analogues represent a novel approach for the treatment of certain cancers. The objective of this article is to summarise the current knowledge on SST analogues in the treatment of cancer patients.
METHODS
Computerised (Medline) and manual searches were performed to identify publications on clinical trials published in the English-speaking literature between 1966 and 2000. Information abstracted included patients' pre-treatment status, histology, SST receptor (SSTR) evaluation, type of SST analogue, application schedule and dose, duration of treatment, side-effects, response criteria applied (i.e. WHO response criteria, biochemical criteria or symptomatic investigations) and survival.
RESULTS
Our search disclosed 22 case reports, five phase 1 and 47 phase II trials, and eight randomised clinical trials using SST analogues (octreotide, lanreotide and vapreotide) as antineoplastic agents. With regard to the phase II trials, conflicting results have been demonstrated in almost all tumour entities investigated. The few randomised studies published so far have shown an impact on survival in patients with hepatocellular cancer, while the effect attributed to treatment in patients with gastrointestinal adenocarcinomas might well have been due to an exceptionally short survival in the control group. There appears to be evidence that SST analogues are able to enhance the therapeutic effects of hormonal intervention in patients with breast cancer, prostate cancer and probably pancreatic cancer. Interpretation of the findings, however, is complicated by the fact that patients were heavily pre-treated in some studies and response criteria have not been uniformly applied. In addition, most studies have not been designed to distinguish between receptor-mediated (direct) and indirect effects of SST analogues in tumour patients.
CONCLUSIONS
According to the results obtained so far, there can be no doubt about the wide therapeutic index and the high efficacy of SST analogues in the symptomatic management of neuroendocrine tumours. Apart from these indications, the data do not justify recommendation of SST analogues as antineoplastic agents outside of clinical trials, as the optimal dose and schedule of application for antineoplastic activity has not been defined for currently used agents. Carefully designed clinical trials including investigation of SSTR status before treatment, evaluation of an indirect mechanism of SST analogues, and assessment of optimal combination of hormone therapy and chemotherapy with SST analogues are clearly needed in the near future.
Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Neoplasms; Octreotide; Peptides, Cyclic; Randomized Controlled Trials as Topic; Sensitivity and Specificity; Somatostatin; Survival Analysis; Treatment Outcome
PubMed: 12075733
DOI: 10.1093/annonc/mdf142 -
Annales D'endocrinologie Apr 2002Somatostatin and its stable analogues (octreotide, lanreotide and vapreotide) exert an antiproliferative effect on various normal and cancerous cells both in vitro and... (Review)
Review
Somatostatin and its stable analogues (octreotide, lanreotide and vapreotide) exert an antiproliferative effect on various normal and cancerous cells both in vitro and in vivo. This effect results from different mechanisms: an indirect effect by the inhibition of release of growth factors and trophic hormones (GH, IGF-1, insulin, gastrin, EGF), an inhibition of angiogenesis processes (endothelial cell proliferation, VEGF release, monocyte activity), an immunomodulatory effect (lymphocyte proliferation, interleukine or cytokine release, NK activity) and a direct effect on target cells. This direct antiproliferative effect is mediated through specific somatostatin receptors. Among them, sst(1), sst(2), sst(4) and sst(5) have been implicated in vitro in the G1-G0 cell cycle blockade, sst(3) and sst(2) mediating the apoptotic effect of somatostatin. In addition, sst(2) acts as an antioncogene in human pancreatic cancer cells. Coupling to membrane tyrosine phosphatases (SHP-1, SHP-2) is the main transduction pathway involved in the antiproliferative effect mediated by sst receptors. The dissociation observed clinically between a frequent antisecretory response and an inconstant antitumor effect after administration of somatostatin analogues may reflect an absence of expression or coupling of the receptor(s) involved in antiproliferative effect. Moreover, a desensitization or mutation of these receptors may also occur in tumors. All the potential mechanism involved should be elucidated in order to improve or better target the antitumor effect of somatostatin analogues clinically used.
Topics: Animals; Cell Division; Hormone Antagonists; Humans; Receptors, Somatostatin; Somatostatin
PubMed: 12037498
DOI: No ID Found -
Clinical Otolaryngology and Allied... Apr 2002Somatostatins are neuropeptides that exert a downregulatory effect on various physiological processes. Somatostatin analogues are used in the imaging and management of... (Review)
Review
Somatostatins are neuropeptides that exert a downregulatory effect on various physiological processes. Somatostatin analogues are used in the imaging and management of various tumour types. Their role in thyroid cancer has not as yet been fully elucidated. A systematic review of the literature using the keywords thyroid, cancer and somatostatin revealed 263 references. This paper summarizes the current knowledge of the role of somatostatins in thyroid cancer and assesses their future potential.
Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Autoradiography; Humans; Octreotide; Peptides, Cyclic; Somatostatin; Thyroid Neoplasms
PubMed: 11994118
DOI: 10.1046/j.1365-2273.2002.00543.x -
Seminars in Nuclear Medicine Apr 2002The authors briefly review radiopeptides currently approved for use in the United States. They present a short review of the peptide somatostatin's actions and also note... (Review)
Review
The authors briefly review radiopeptides currently approved for use in the United States. They present a short review of the peptide somatostatin's actions and also note the five somatostatin receptors (SSTRs) to which the peptide and its synthetic analogs octreotide, lanreotide, and vapreotide bind. The many conditions besides neuroendocrine tumors having SSTRs are listed. Labeled octreotide and the other two analogues have a strong affinity for SSTR2 and SSTR5, which thereby produce positive imaging. The various neuroendocrine tumors best imaged by somatostatin receptor scintigraphy (SRS) are discussed, and the exceptions (insulinoma and medullary thyroid carcinoma) are noted to be seen better with labeled VIP and (99m)Tc-dimethylsuccinic acid (DMSA), respectively. SRS and VIP receptor scintigraphy are also noted to image many nonneuroendocrine tumors, which often have appropriate receptors. Several of the currently emerging and very effective new imaging techniques are described. These include (99m)Tc-DMSA for medullary thyroid carcinoma, (18)F dihydroxyphenylalanine positron emission tomography, and C(11) 5-hydroxytryptophan positron emission tomography scanning for all neuroendocrine tumor, but especially carcinoid tumor, metastases. The special role of SRS in identifying gastric carcinoid tumors in hypergastrinemic patients is reviewed. Various pitfalls in interpreting SRS are presented and receptor-enhancing techniques described. Besides use of SRS (mainly Octreoscan, Mallinckrodt Medical, St. Louis, MO) only for detecting and localizing primary tumors and metastases for staging, there are many additional special uses for clinical management of SRS-positive tumors. These include the intraoperative use of the handheld gamma-detecting probe. A brief enumeration is given of the most promising of other non-SST G-protein-coupled receptors and ligands currently under development. Finally, we have posed a number of questions for which answers are needed in the immediate future to facilitate better imaging. Extrapolations of current knowledge and experience with radiolabeled peptide pharmaceutical imaging are converted to reasonable speculations of anticipated future developments in this field.
Topics: Humans; Indium Radioisotopes; Neuroendocrine Tumors; Octreotide; Peptides, Cyclic; Radioisotopes; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin
PubMed: 11965602
DOI: 10.1053/snuc.2002.31020 -
Journal of Medicinal Chemistry Apr 2002Somatostatin-14 (somatostatin) and its clinically available analogues octreotide, lanreotide, and vapreotide are potent inhibitors of growth hormone, insulin, and...
Somatostatin-14 (somatostatin) and its clinically available analogues octreotide, lanreotide, and vapreotide are potent inhibitors of growth hormone, insulin, and glucagon release. Recently, a novel backbone cyclic somatostatin analogue c(GABA-Phe-Trp-(D)Trp-Lys-Thr-Phe-GlyC3-NH(2)) (analogue 1, PTR 3173) that possesses in vivo endocrine selectivity was described. This long-acting octapeptide exhibits high affinity to human recombinant somatostatin receptors (hsst) hsst2, hsst4, and hsst5. Its novel binding profile resulted in potent in vivo inhibition of growth hormone but not of insulin release. We report the synthesis, bioactivity, and structure-activity relationship studies of compounds related to 1. In these analogues, the lactam bridge of 1 was replaced by a backbone disulfide bridge. We present a novel approach for conformational constraint of peptides by utilizing sulfur-containing building units for on-resin backbone cyclization. These disulfide backbone cyclic analogues of 1 showed significant metabolic stability as tested in various enzyme mixtures. Receptor binding assays revealed different receptor selectivity profiles for these analogues in comparison to their prototype. It was found that analogues of 1, bearing a disulfide bridge, had increased selectivity to hsst2 and hsst5; however, they exhibited weaker affinity to hsst4 as compared to 1. These studies imply that ring chemistry, ring size, and ring position of the peptide template may affect the receptor binding selectivity.
Topics: Animals; CHO Cells; Cloning, Molecular; Cricetinae; Disulfides; Drug Stability; Humans; In Vitro Techniques; Kidney; Liver; Molecular Conformation; Peptides, Cyclic; Radioligand Assay; Rats; Receptors, Somatostatin; Somatostatin; Structure-Activity Relationship
PubMed: 11931620
DOI: 10.1021/jm0100281 -
Hepatology (Baltimore, Md.) Mar 2002Endoscopic therapy, involving either injection sclerosis or band ligation, is considered the intervention of first choice for acute variceal bleeding (AVB).... (Comparative Study)
Comparative Study Meta-Analysis
Endoscopic therapy, involving either injection sclerosis or band ligation, is considered the intervention of first choice for acute variceal bleeding (AVB). Pharmacologic agents have also been shown to be highly effective in the control of the bleeding episode. The purpose of this meta-analysis was to assess whether vasoactive drugs may improve the efficacy of endoscopic therapy (injection sclerosis or band ligation) in the control of AVB and thus increase survival rates. Computer databases and scientific meeting abstracts from 1994 to 2001 were used to search for randomized trials that compared the combined use of endoscopic and drug therapy with endoscopic therapy alone in the control of AVB. Eight trials involving 939 patients fulfilled the selection criteria and the following evaluated by standard meta-analysis methods: initial hemostasis, 5-day hemostasis, 5-day mortality, and adverse events. Combined treatment improved initial control of bleeding (relative risk [RR], 1.12; 95% confidence interval (CI), 1.02-1.23), and 5-day hemostasis (RR, 1.28; 95% CI, 1.18-1.39), with numbers of patients needed to treat (NNT) of 8 and 5, respectively. The difference in favor of combined treatment remained significant when trials that used drugs other than octreotide or that included a low proportion of alcoholic patients (<40%) or high-risk cirrhotic patients (<35%) were excluded. Mortality was not significantly decreased by combined therapy (RR, 0.73; 95% CI, 0.45-1.18). Severe adverse events were similar in both groups. In conclusion, in patients with AVB, pharmacologic agents improve the efficacy of endoscopic therapy to achieve initial control of bleeding and 5-day hemostasis, yet fail to affect mortality.
Topics: Acute Disease; Combined Modality Therapy; Endoscopy; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemostasis; Humans; Octreotide; Somatostatin; Vasoconstrictor Agents
PubMed: 11870374
DOI: 10.1053/jhep.2002.31354 -
Gastrointestinal Endoscopy Jan 2002
Topics: Combined Modality Therapy; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Male; Recurrence; Risk Factors; Somatostatin
PubMed: 11789479
DOI: 10.1016/s0016-5107(02)99991-8