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

The somatostatin analog TT-232 containing a 5 residue ring, was previously shown to inhibit the proliferation of a large number of cancer cell lines in vitro and reduce the size of tumors in animal models in vivo. Its action is accompanied by inhibition of tyrosine kinases and is characterized by the induction of programmed cell death. On the other hand, it was proved to be free of the endocrine effects of the natural compound. The aim of this study was to find the optimal dose and administration route for in vivo tumor therapy in an animal model. We have investigated the dose--and administration route-dependent antitumor activity of TT-232 on S-180 sarcoma tumor transplanted to inbred BDF1 mice from SPF breeding. Long-term administration (i.p., s.c. and i.v. injections) was started either on the day subsequent to tumor transplantation or after the development of tumor. The antineoplastic potential of TT-232 was evaluated on the basis of survival and tumor growth inhibition. In long-term administration (injections twice a day for 2 weeks) a significant, but dose- and administration route-dependent therapeutic efficacy of TT-232 was observed. The optimum dose of TT-232 15 micrograms/kg which resulted in a 30-40% cure rate and 50-70% growth inhibition in S-180 sarcoma tumor. A moderate antitumor effect was achieved by TT-232 when it was administered after the evelopment of tumor. Our study suggests that TT-232 can be a promising antitumor agent.
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PMID:In vivo antitumor activity of TT-232 a novel somatostatin analog. 1065 22

Gastrin is a hormone regulating gastric acid secretion and the growth of the gastrointestinal epithelium. It is expressed by endocrine tumors and by adenocarcinomas of the gastroenteropancreatic region and may represent an autocrine tumor growth factor. Gastrin is also implicated in the genesis of peptic ulcer disease both in conjunction with H. pylori infections and with gastrin-producing tumors. The secretion and expression of gastrin are under the paracrine control of somatostatin, produced by D cells situated in close contact with gastrin-producing G cells. D cells also contain neuronal nitric oxide synthase and appear to regulate apoptosis of G cells by paracrine release of nitric oxide. Both G and D cells are derived from a common multihormonal precursor cell present in the regenerative (isthmus) region of the gastric units. The precursor cells have been suggested to undergo asymmetrical divisions resulting in gastrin- and somatostatin-producing daughter cells that remain in paracrine contact during their migration into the glands. The precursor cells also give rise to the third main antropyloric endocrine cell type; the serotonin-producing EC cell. The maturation of all of these cell types is regulated by a number of transcription factors containing homeobox motifs (Pdx-1, Pax 4 and 6, Isl-1, Nkx6.1). Many of these also regulate the development of the central nervous system and the pancreas. The use of different combinations of these factors for regulating the expression of different hormones may explain the phenomenon of abberant hormone expression during development and carcinogenesis and the occurrence of multihormonal cells.
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PMID:Developmental biology of gastrin and somatostatin cells in the antropyloric mucosa of the stomach. 1070 44

TT-232 a novel tumor-selective somatostatin analog with a five residue ring structure (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2) was developed by us and published in an earlier work. This synthetic heptapeptide had no effect on growth hormone release, but had a remarkable tyrosine-kinase inhibitory effect and inducted apoptosis. The aim of this study was to compare the therapeutic efficacy of TT-232 used in various long-term administration routes and treatment schedules. The effectiveness of TT-232 was studied on different rodent tumors transplanted to inbred mice from SPF breeding. Intermittent treatment by injections and continuous infusion of TT-232 using a s.c., i.p. or i.v. implanted Alzet type osmotic minipump were compared for therapeutic efficacy. The treatments were started either on the day subsequent to tumor transplantation or after the development of a tumor. On the basis of survival and tumor growth inhibition the infusion of TT-232 for 14 days using an implantable osmotic pump proved to be a much more effective route of treatment in both s.c. and i.v. administration than the intermittent injections applied twice a day for 2 weeks. In the case of S-180 sarcoma the continuous administration of TT-232 for 14 days using s.c. implanted osmotic pump resulted in 60% the i.v. infusion produced 40% long-term (over 80 days) and tumor free survivors. By the continuous administration of TT-232, an 80-100% tumor growth inhibitory effect and a considerable retardation of tumor development could be achieved. Continuous infusion from implanted pumps ensured a constant drug level and resulted in a well-defined, consistent pattern of drug exposure over the full duration of drug administration. In our study the route of infusion has been shown to increase drug efficacy relative to conventional delivery methods.
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PMID:Influence of various administration routes on the antitumor efficacy ofTT-232, a novel somatostatin analog. 1081 Mar 91

The effectiveness of chemotherapy targeted to somatostatin (SST) receptors based on cytotoxic SST analogue AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to SST carrier octapeptide, was investigated in human renal cell carcinomas (RCCs). SST receptors, which showed high-affinity binding for AN-238, were found in the SW-839 RCC line with sst2A subtype and in the 786-0 RCC line, which expressed the sst5 subtype. CAKI-1 RCC, which does not express sst2A or sst5, was used as a negative control for testing the specificity of SST receptor targeting. Using microsatellite analysis, AN-238 was shown to selectively inhibit the proliferation of 786-0 line, but not the CAKI-1 RCC line in vitro. The effects of three i.v. injections of 150 nmol/kg of AN-238 or AN-201, given on days 1, 8, and 21, were evaluated in groups of nude mice bearing s.c. xenografts of SW-839 and 786-0 RCC. After 5 weeks, the volumes of SW-839 and 786-0 RCC tumors were decreased by 67.2 (P < 0.05) and 78.3% (P < 0.01), respectively, whereas AN-201 had no significant effect on tumor growth. The inhibition of SST receptor-negative CAKI-1 tumors by AN-238 was only marginal. To investigate the efficacy of SST receptor-targeted chemotherapy in metastatic RCC, three i.v. injections of AN-238 or AN-201 at 150 nmol/kg were given at biweekly intervals to nude mice implanted with 786-0 tumors under the renal capsule. After 6 weeks, the weight of orthotopic tumors treated with AN-238 (55.3 +/- 44.3 mg) was significantly lower (87% reduction; P < 0.001) than that in the control group (414.2 +/- 41.0 mg) or in animals given AN-201 (270.2 +/- 603 mg; P < 0.05). Five of six animals (83%), both in the control and the AN-201 group, developed metastases to lymph nodes, but only one of seven mice (14%) given AN-238 showed lymphatic spread. Lung metastases were found in 83% of controls and 50% of AN-201 treated animals, but none occurred in mice treated with AN-238. This study demonstrates that targeted cytotoxic SST analogue AN-238 provides an effective therapy for chemoresistant neoplasms such as RCC. Because most clinical RCCs express SST receptors, this treatment modality might be beneficial to patients with metastatic disease.
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PMID:Inhibition of metastatic renal cell carcinomas expressing somatostatin receptors by a targeted cytotoxic analogue of somatostatin AN-238. 1085 Apr 48

We developed a group of synthetic analogs of GnRH and Somatostatin to inhibit the tumor growth of different kind. The GnRH analogs decreasing the gonadotroph and steroid hormone levels act on the hormone dependent tumors and influence their growth. One of the most effective antitumor analog was patented under the name FOLLIGEN which inhibited the breast cancer caused by DMBA in rats without any side-effects. Other inhibitory analogs of GnRH with long-lasting effect were effective in the treatment of breast, ovary and prostate tumors. Another analog [alpha-Asp(DEA)]6,Gln8-hGnRH showed a very low endocrine but high antitumor effect in both in vitro and in vivo experiments. Its tritium labeled derivative exhibited specific binding sites on human tumor cell lines. We synthesized the analogs of GnRH-III with effective selective antitumor activity which does not alter the ovarian cycle of rats but inhibits the colony-formation of human breast cancer cell lines and has a significant antiproliferative effect. We also synthesized conjugates of potent GnRH analogs with a branched chain polylysine backbone which induce a 33-35% decrease of cell numbers of MCF-7 and MDA-MB-231 human breast cancer cell lines and 45-50% inhibition of cell proliferation. Another conjugate decreased the tumor growth of MDA-MB-231 xenografts by 80% in a treatment of 9 weeks and even tumor free animals could be found among the ones treated. Using these radiolabeled peptide hormone analogs we found that human tumor cell lines and xenografts specifically bind the GnRH conjugates. We also synthesized a series of Somatostatin analogs which inhibit tyrosine kinases and the growth of several breast, prostate and colon tumor cell lines. One of our best analogs was a heptapeptide, TT-232, which strongly inhibited the tyrosine kinase activity and the cell-proliferation in different colon tumor cells. However, it did not inhibit the growth hormone release either in vitro or in vivo from rat pituitary cells. The TT-232 was found to be effective on 60 human tumor cell lines, it significantly inhibited the tumor growth on different animal tumor models, and induced apoptosis, as a result of which some animals became tumor free. The TT-232 inhibited the tumor growth of PC3 prostate xenografts with 60% and caused a 100% survival of mice 60 days after the transplantation. It is being preclinically tested at present. We have shown that the new GnRH analogs acting without any hormonal effect and the Somatostatin analogs with strong antitumor and tyrosine kinase inhibitory activity but no hormonal effect may represent a breakthrough in the research of the antitumor peptides, having direct effect on tumor cells.
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PMID:Peptides and antitumor activity. Development and investigation of some peptides with antitumor activity. 1086 57

Neuroendocrine tumors include carcinoids and pancreatic endocrine tumors, which share a number of common features in their pathology, ability to cause clinical symptoms due to ectopic hormone and bioamine release, localization methods, and treatment. Although generally slow growing, a proportion demonstrate aggressive tumor growth. Therefore, in many cases treatment must be directed against both the tumor and the hormone-excess state. There have been significant recent advances into their molecular pathogenesis, natural history, and prognostic factors; clinical presentation defined by larger series analysis; localization methods; and the development of new treatments directed against the tumor and to control the hormone-excess state (including depot somatostatin analogues, interferon combinations, embolization, chemoembolization, radiotherapy with novel somatostatin analogues, and liver transplantation). Recent advances in each of these areas are briefly discussed.
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PMID:Carcinoid and pancreatic endocrine tumors: recent advances in molecular pathogenesis, localization, and treatment. 1088 24

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.
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PMID: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. 1090 Feb 62

Neuroendocrine gastroenteropancreatic tumors are rather rare neoplasms with an incidence of 1-2 cases per 100,000 people. They show rather varying tumor biology and present sometimes distinct clinical symptoms such as flushing, diarrhoea, hypoglycemia and gastric ulcers. The biochemical diagnosis is today significantly improved by the introduction of chromogranin A as a general tumor marker, which is also useful in histopathology. Today the localization procedures include somatostatin receptor scintigraphy as the primary investigation together with CT or ultrasonography. The basis for treatment of neuroendocrine GEP tumors is not only a curative intent but merely amelioration of clinical symptoms, abrogation of tumor growth, maintaining and improvement of quality of life. Surgery has always to be considered in the treatment of neuroendocrine GEP tumors. It can be performed whenever during the course of the disease but it may be more productive in earlier stages. Liver dearterialization procedures can furthermore reduce the tumor masses in liver together with laser treatment or radiofrequency therapy. The medical treatment includes cytotoxic agents, alpha interferons and somatostatin analogues. Somatostatin analogues will always be combined with the other two alternatives to reduce clinical symptoms. Chemotherapy is particularly useful for patients with more aggressive tumors with high proliferation capacity, whereas alpha interferon is beneficial in classical midgut carcinoids with low proliferation capacity. Quite recently somatostatin based radioactive tumor targeted treatment has evolved with preliminary promising data but further studies are needed to deliniate its future role in the treatment of neuroendocrine tumors in patients.
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PMID:State of the art and future prospects in the management of neuroendocrine tumors. 1093 97

Angiogenesis is known to be a critical process for the tumor growth and metastasis. There are many indigenous role-players in tumor angiogenesis and anti-angiogenesis, where tumor-host interaction may work. A lot of agents with anti-angiogenic activity have been developed for anti-cancer treatment. Several agents including Marimastat, Primostat, Neovastat, Bay-12-9566m, Interferon-alpha, SU101, retinoids, and IM862, are/were under phase-three study. There are still many future-promising results of basic or clinical studies on inhibitors of MMPs, and inhibitors of VEGF/R, Endostatin, somatostatin analogues, COX-2 inhibitors, and others. Most of the combination treatments of antiangiogenetic agent and conventional anticancer agents therapy, or radiation therapy as we reported, showed relatively small or minute increase in toxicity of these cytotoxic treatments.
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PMID:[Recent studies on anti-angiogenesis in cancer therapy]. 1094 47

Thyroid hormone inhibits thyrotropin (TSH) production and thyrotrope growth. Somatostatin has been implicated as a synergistic factor in the inhibition of thyrotrope function. We have previously shown that pharmacological doses of thyroid hormone (levothyroxine [LT4]) inhibit growth of murine TtT-97 thyrotropic tumors in association with upregulation of somatostatin receptor type 5 (sst5) mRNA and somatostatin receptor binding. In the current study, we examined the effect of physiological thyroid hormone replacement alone or in combination with the long-acting somatostatin analogue, Sandostatin LAR, on thyrotropic tumor growth, thyrotropin growth factor-beta (TSH-beta), and sst5 mRNA expression, as well as somatostatin receptor binding sites. Physiological LT4 replacement therapy resulted in tumor shrinkage in association with increased sst5 mRNA levels, reduced TSH-beta mRNA levels and enhanced somatostatin receptor binding. Sandostatin LAR alone had no effect on any parameter measured. However, Sandostatin LAR combined with LT4 synergistically inhibited TSH-beta mRNA production and reduced final tumor weights to a greater degree. In this paradigm, Sandostatin LAR required a euthyroid status to alter thyrotrope parameters. These data suggest an important interaction between the somatostatinergic system and thyroid hormone in the regulation of thyrotrope cell structure and function.
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PMID:The effect of thyroid hormone and a long-acting somatostatin analogue on TtT-97 murine thyrotropic tumors. 1095 5


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