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Chemotherapy 2001Due to the limited efficacy and considerable toxicity of conventional chemotherapy, novel cytotoxic agents and innovative noncytotoxic approaches to cancer treatment are... (Review)
Review
Due to the limited efficacy and considerable toxicity of conventional chemotherapy, novel cytotoxic agents and innovative noncytotoxic approaches to cancer treatment are being developed. Amongst the various hormonal agents, increasing attention is being directed to somatostatin analogs. This is largely due to the demonstration of antineoplastic activity of these compounds in a variety of experimental models in vitro and in vivo and to the elucidation of some aspects of the molecular mechanisms underlying their antineoplastic activity. On the other hand, clinical experience with somatostatin analogs in the treatment of conditions like acromegaly and GEP tumors has shown that they are well tolerated compared to other antineoplastic therapies currently in use. As a consequence, there is much ongoing clinical research to determine whether or not results from experimental studies will translate into clinically useful antineoplastic activity. Besides being used in cancer treatment and palliation, radiolabelled somatostatin analogs are employed for the localization of primary and metastatic tumors expressing somatostatin receptors. The so-called 'somatostatin receptor scintigraphy' is indeed the most important clinical diagnostic investigation for patients with suspected neuroendocrine tumors. Targeted radiotherapy, which is being evaluated in clinical trials, represents an obvious extension of somatostatin scintigraphy. Since the short half-life of native somatostatin makes continuous intravenous infusion mandatory, several long-acting analogs have been synthesized. Amongst the hundreds of peptides synthesized, octreotide (which binds mainly to SSTR-2 and SSTR-5 receptor subtypes) has been the most extensively investigated. A thorough analysis of the pharmacological activities and therapeutic efficacy of the native somatostatin and the synthetic analogs (octreotide, lanreotide and vapreotide) reveals that the biological actions of these peptides are not always identical. These differences appear to be related to the different affinities of the natural hormone and synthetic derivatives for the different receptor subtypes. For all the three peptides long-lasting formulations have been developed to provide patients with the convenience of once or twice a month administration and to ensure stable drug serum concentrations between injections. Radiolabelled derivatives of octreotide, lanreotide and vapreotide have been synthesized and used as radiopharmaceuticals for somatostatin receptor scintigraphy and somatostatin receptor-targeted radiotherapy. The safety profile of synthetic somatostatin analogs is well established. Most adverse reactions to these peptides are merely a consequence of their pharmacological activity and consist mainly of gastrointestinal complaints, cholelithiasis and effects on glucose metabolism. They are often of little clinical relevance, thus making somatostatin analogs safe drugs for long-term use. While immediate release preparations are the drugs of choice in the short term, long-acting formulations are better indicated, on an outpatient basis, for the long-term management of chronic conditions. New 'receptor-selective' and 'universal' somatostatin analogs are being developed and combinations of currently available derivatives with other (cytotoxic and/or hormonal) agents are being explored in the search for an efficacious and well-tolerated treatment of the various malignancies. Somatostatin receptor-targeted chemotherapy (with conjugates of somatostatin peptides with cytotoxic drugs) and gene therapy (e.g. transferring the SSTR-2 gene into neoplastic cells), which have been successfully tested in experimental studies, should be applied to human beings in a not too distant future.
Topics: Animals; Humans; Neoplasms; Radionuclide Imaging; Radiopharmaceuticals; Somatostatin
PubMed: 11275699
DOI: 10.1159/000049157 -
Life Sciences Mar 2000Oral cancer which comprises about 40% of total cancers in India, has one of the lowest relative survival rates of all cancers. Epidermal growth factor (EGF) has been...
Oral cancer which comprises about 40% of total cancers in India, has one of the lowest relative survival rates of all cancers. Epidermal growth factor (EGF) has been known to play a role in the proliferation/malignant transformation of oral neoplasms. Since, the somatostatin analog RC-160 is reported to be a potent inhibitor of EGF stimulated cell proliferation, its anti-proliferative activity in the human oral carcinoma cell line KB was investigated, in this study. RC-160 was found to potently inhibit EGF-induced proliferation in KB cells in vitro, suggesting a therapeutic potential of the same in oral carcinoma. However, the therapeutic potential of RC-160 is limited by its short serum half life. To overcome this limitation, fatty acids namely butanoic acid and myristic acid individually were coupled to RC-160. The lipophilized derivatives of RC-160 were synthesized, purified and characterized. The anti-proliferative activity of lipophilized derivatives of RC-160 on KB cells was evaluated in vitro. Myristoyl-RC-160 (0.75 nM) inhibited the growth of KB cells at a 10-fold lower concentration relative to RC-160 (8.8 nM) and at a 100-fold lower concentration relative to butanoyl-RC-160 (0.83 microM) (p<0.001). The affinity of RC-160 towards somatostatin receptors remains unaltered by lipophilization. The signaling pathways underlying the antineoplastic activity of these lipopeptides are similar to RC-160, and do not involve the stimulation of a protein tyrosine phosphatase or a serine threonine phosphatase 1A and 2A. The anti-proliferative activity of the lipopeptides was found to be mediated by somatostatin receptors and correlates with the inhibition of protein tyrosine kinase activity and decrease in intracellular cAMP levels. Myristoyl-RC-160 displayed significantly greater resistance towards trypsin and serum degradation than RC-160 (p<0.01). These findings demonstrate that RC-160 can inhibit the growth of oral cancer cells in vitro. Lipophilization of RC-160 with long chain fatty acids like myristic acid improves its stability and anti-proliferative activity, in human oral carcinoma cells in vitro, thereby enhancing the scope of improving its therapeutic index.
Topics: Antineoplastic Agents, Hormonal; Butyric Acid; Cell Division; Cyclic AMP; Fatty Acids; GTP-Binding Proteins; Humans; KB Cells; Mouth Neoplasms; Myristic Acid; Protein-Tyrosine Kinases; Receptors, Somatostatin; Somatostatin; Trypsin
PubMed: 11261586
DOI: 10.1016/s0024-3205(00)00476-8 -
Journal of Endocrinological... Jan 2001Antagonism between GH secretagogues (GHS) and somatostatin (SRIH) has been postulated and demonstrated, but SRIH does not bind to GHS receptors (GHS-R) and potent...
Antagonism between GH secretagogues (GHS) and somatostatin (SRIH) has been postulated and demonstrated, but SRIH does not bind to GHS receptors (GHS-R) and potent synthetic peptidyl GHS (GHRP6, hexarelin) do not displace radiolabeled SRIH from its receptors. However, non-natural SRIH octapeptide agonists (mainly lanreotide and vapreotide) displace 125I-Tyr-Ala-hexarelin from pituitary binding sites suggesting that an endogenous factor related to SRIH might exist and interact with GHS-R. Our aims were to investigate the ability of different SRIH-like peptides such as various SRIH fragments (SRIH 3-14, SRIH 7-14, SRIH 3-10, SRIH 7-10, SRIH 2-9) and a natural neuropeptide that shows a high structural homology with SRIH such as cortistatin-14 (CST) to compete with 125I-Tyr-Ala-hexarelin for human pituitary binding sites and to compare their binding affinity with that of hexarelin and ghrelin, a gastric-derived peptidyl GHS that has been proposed as a natural ligand of GHS-R. While the binding of 125I-Tyr-Ala-hexarelin to pituitary membranes was completely displaced by unlabelled hexarelin, ghrelin and CST, none of the SRIH fragments tested inhibited this binding. Ghrelin and CST exhibited a similar affinity (4.6-5.4 x 10(-7) mol/l) for the binding while hexarelin was more effective by about four orders of magnitude in displacing 125I-Tyr-Ala-hexarelin. Our data demonstrate for the first time that cortistatin, a natural peptide related to SRIH, binds to GHS-R and suggest that this factor may play a role in modulating the activity of these receptors.
Topics: Adult; Binding, Competitive; Cell Membrane; Female; Ghrelin; Humans; Male; Middle Aged; Neuropeptides; Oligopeptides; Peptide Hormones; Peptides; Pituitary Gland; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Somatostatin
PubMed: 11227737
DOI: 10.1007/BF03343800 -
Journal of Hepato-biliary-pancreatic... 2000The antiproliferative effects of somatostatin and its analogs on human pancreatic cancers were studied: (1) by evaluating the gene expression of somatostatin receptor...
The antiproliferative effects of somatostatin and its analogs on human pancreatic cancers were studied: (1) by evaluating the gene expression of somatostatin receptor (sstr) subtypes in human pancreatic cancer cell lines and cancer tissue specimens, (2) by evaluating the antiproliferative effects of somatostatin analogs, and (3) by evaluating the effect of sstr-2 cDNA transduction. Using a reverse transcriptase polymerase chain reaction (RT-PCR), the gene expression of five sstr subtypes (sstr-1 to -5) was examined in eight cell lines, and in ten pancreatic cancer tissues and in the normal surrounding pancreatic tissues. The antiproliferative effects of somatostatin (SS) -14 and its two analogs (SMS 201-995, RC-160) were examined by means of an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (thiazolyl blue)) assay on three cell lines and Panc-1 transfectants with human sstr (hsstr)-2A cDNA. Sstr-2 was expressed in all samples tested. All examined cell lines simultaneously expressed sstr-2 and -5, while most of the examined pancreatic cancer tissues did not express both of these subtypes simultaneously. Somatostatin analogs inhibited epidermal growth factor (EGF)-stimulated pancreatic cancer cell proliferation. The cell proliferation was further and significantly inhibited by 14% in stable transfectants of Panc-1 cells with hsstr-2A. Based on these findings, it is concluded that somatostatin analogs with their antiproliferative effects mediated by sstr-2 could be potentially useful in the treatment of pancreatic cancers.
Topics: Cell Division; Humans; Octreotide; Pancreatic Neoplasms; Receptors, Somatostatin; Reverse Transcriptase Polymerase Chain Reaction; Somatostatin; Tumor Cells, Cultured
PubMed: 11180877
DOI: 10.1007/s005340070021 -
The New England Journal of Medicine Jan 2001In patients with cirrhosis, pharmacologic or endoscopic treatment may control variceal bleeding. However, the effects of early administration of a somatostatin analogue... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
In patients with cirrhosis, pharmacologic or endoscopic treatment may control variceal bleeding. However, the effects of early administration of a somatostatin analogue followed by endoscopic treatment are unknown.
METHODS
We studied the effects of treatment with vapreotide, a somatostatin analogue, begun before endoscopic treatment in 227 patients with cirrhosis who were hospitalized for acute upper gastrointestinal bleeding. The patients were randomly assigned to receive vapreotide (a 50-microg intravenous bolus followed by an infusion at a rate of 50 microg per hour for five days) or placebo within a mean (+/-SD) of 2.3+/-1.5 hours after admission. All the patients received endoscopic treatment a mean of 2.6+/-3.3 hours after the infusion was begun. After the exclusion of 31 patients whose bleeding was not caused by portal hypertension, there were 98 patients in each group.
RESULTS
At the time of endoscopy, active bleeding was evident in 28 of 91 patients in the vapreotide group (31 percent), as compared with 43 of 93 patients in the placebo group (46 percent) (P=0.03). During the five-day infusion, the primary objective--survival and control of bleeding--was achieved in 65 of 98 patients in the vapreotide group (66 percent) as compared with 49 of 98 patients in the placebo group (50 percent) (P=0.02). The patients in the vapreotide group received significantly fewer blood transfusions (2.0+/-2.2 vs. 2.8+/-2.8 units, P=0.04). Overall mortality rates at 42 days were not significantly different in the two groups.
CONCLUSIONS
In patients with cirrhosis and variceal bleeding, the combination of vapreotide and endoscopic treatment is more effective than endoscopic treatment alone as a method of controlling acute bleeding. However, the use of combination therapy does not affect mortality rates at 42 days.
Topics: Blood Transfusion; Combined Modality Therapy; Endoscopy; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Multivariate Analysis; Sclerotherapy; Secondary Prevention; Somatostatin
PubMed: 11136956
DOI: 10.1056/NEJM200101043440104 -
Oncology 2000In this study, we investigated the effects of somatostatin analog RC-160 on the growth of the OV-1063 human epithelial ovarian cancer cell line in vitro. RC-160...
In this study, we investigated the effects of somatostatin analog RC-160 on the growth of the OV-1063 human epithelial ovarian cancer cell line in vitro. RC-160 inhibited cell proliferation, as measured by cell number, and [(3)H]thymidine incorporation into DNA at 10(-9)-10(-5) M. In OV-1063 cells, (125)I-labeled RC-160 was bound to one class of specific, saturable binding sites with high affinity (K(d) = 0.2 +/- 0.03 nM) and low capacity (5,500 binding sites per cell). (125)I-labeled RC-160 could be displaced by unlabeled RC-160. Ligand binding was dependent on time and temperature. Receptor internalization assay showed that the ligand-receptor complex was internalized at 37 degrees C, which indicates the presence of biologically active somatostatin receptors on OV-1063 cells. These results suggest that somatostatin analog RC-160 can suppress the growth of OV-1063 human epithelial ovarian cancer cells by a direct action and that the inhibitory effect of somatostatin analog is mediated through the high-affinity somatostatin receptors.
Topics: Antineoplastic Agents; Carcinoma; Cell Division; Female; Humans; Iodine Radioisotopes; Ovarian Neoplasms; Receptors, Somatostatin; Somatostatin; Tumor Cells, Cultured
PubMed: 11096356
DOI: 10.1159/000055287 -
Orvosi Hetilap Oct 2000The authors give an overview on the clinical treatment results of pancreatic carcinoma with somatostatin analogs including octreotide, lanreotide and vapreotide.... (Review)
Review
The authors give an overview on the clinical treatment results of pancreatic carcinoma with somatostatin analogs including octreotide, lanreotide and vapreotide. Numerous preclinical studies provided solid evidence that the growth of ductal pancreatic adenocarcinoma can successfully be inhibited using such synthetic analogs via direct (apoptosis-inducing) and various indirect mechanisms. In the clinical practice their role still remains contradictory. Monotherapy did not result in a prolongation of the survival, however, in 15-20% of patients the progression of the process has been halted for several months accompanied by a significant improvement of the clinical condition without notable side effects. Combination of octreotide with tamoxifen yielded a survival benefit in addition to the stabilization of the general condition, although reduction of the tumor mass has not been documented. Despite the modest results these finding reinforce the responsiveness of the pancreatic ductal cancer to the hormonal manipulations and further studies on optimization of the effects are of worth. While in the majority of cases the somatostatin receptors have been lost, hormonal control of the pancreatic cancer could be achieved by combination treatment modalities.
Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Humans; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Receptors, Somatostatin; Somatostatin
PubMed: 11089387
DOI: No ID Found -
The Journal of Clinical Endocrinology... Oct 2000Characteristics of receptors for somatostatin (SST) analog RC-160 on 17 surgical specimens of human epithelial ovarian cancer and two human ovarian cancer lines were... (Clinical Trial)
Clinical Trial
Characteristics of receptors for somatostatin (SST) analog RC-160 on 17 surgical specimens of human epithelial ovarian cancer and two human ovarian cancer lines were determined by ligand competition assays. The expression of mRNA for four SST receptor subtypes (sst1, sst2A, sst3 and sst5) was investigated by RT-PCR. Thirteen of 17 specimens (76%) exhibited high affinity binding sites for RC-160 with Kd = 6.55 nmol/L and a Bmax = 575.4 fmol/mg membrane protein. Specific receptors for RC-160 were also found in xenografts of OV-1063 and UCI-107 human ovarian cancer lines. The mRNA for sst1 was detected in 65% of the ovarian cancer specimens, while the incidence of sst2A, sst3 and sst5 was 65%, 41% and 24%, respectively. Both ovarian cancer cell lines also expressed mRNA for these four subtypes. The presence of these SST receptor subtypes in human ovarian cancers allows the use of SST analogs and their radionuclide and cytotoxic derivatives for the diagnosis and treatment of this malignancy.
Topics: Adult; Aged; Animals; Cell Line; Female; Humans; Membranes; Mice; Mice, Nude; Middle Aged; Ovarian Neoplasms; RNA, Messenger; RNA, Neoplasm; Radioligand Assay; Radiopharmaceuticals; Receptors, Somatostatin; Reverse Transcriptase Polymerase Chain Reaction; Somatostatin; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 11061491
DOI: 10.1210/jcem.85.10.3509 -
Endocrinology Sep 2000Somatostatin analogs labeled with radionuclides are of considerable interest in nuclear oncology as diagnostic or therapeutic tools for somatostatin receptor... (Comparative Study)
Comparative Study
Preclinical comparison in AR4-2J tumor-bearing mice of four radiolabeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-somatostatin analogs for tumor diagnosis and internal radiotherapy.
Somatostatin analogs labeled with radionuclides are of considerable interest in nuclear oncology as diagnostic or therapeutic tools for somatostatin receptor (SSTR)-expressing tumors. We investigated the suitability of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) as a replacement for the widely used diethylenetriaminepentaacetic acid, to enable stable labeling of somatostatin analogs with both therapeutic (90Y) and diagnostic (111In) radionuclides. The three clinically relevant somatostatin agonists, octreotide, vapreotide, and lanreotide, together with the newly designed Tyr3-octreotide (TyrOc), were conjugated to DOTA and labeled with 90Y or 111In. For all DOTA-somatostatin analogs tested, irrespective of the incorporated radionuclide, we observed favorable biodistribution profiles in AR4-2J tumor-bearing mice: 1) a rapid clearance from all SSTR-negative tissues except kidney; 2) a specific uptake in SSTR-positive tissues, including tumor; and 3) an excellent tumor penetration. The main route of excretion was via the kidneys. Nevertheless, DOTATOC was clearly superior to the other DOTA-somatostatin analogs tested, as well as OctreoScan, as indicated by the highest tumor-to-nontarget-tissue ratio, including the tumor-to-SSTR-positive-tissue ratios. The presence of different SSTR subtypes in the SSTR-positive tissues possibly contributes to these differential uptakes. We assume that the very favorable behavior of DOTATOC in our mouse model makes this radioligand very promising for future applications in nuclear oncology.
Topics: Animals; Chelating Agents; Chromatography, High Pressure Liquid; Female; Heterocyclic Compounds, 1-Ring; Hormone Antagonists; Indium Radioisotopes; Kidney; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; RNA, Messenger; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin; Tissue Distribution; Yttrium Radioisotopes
PubMed: 10965902
DOI: 10.1210/endo.141.9.7683 -
Cancer Research Aug 2000Targeting chemotherapy selectively to cancers can reduce the toxic side effects. AN-152, a conjugate of doxorubicin and [D-Lys6]-luteinizing hormone-releasing hormone...
Targeting chemotherapy selectively to cancers can reduce the toxic side effects. AN-152, a conjugate of doxorubicin and [D-Lys6]-luteinizing hormone-releasing hormone (LH-RH), is more potent against LH-RH receptor-bearing cancers and produces less peripheral toxicity than doxorubicin. Many cancers, e.g., 50% of breast cancers, but few normal tissues express these receptors, providing a selective target for this cytotoxic conjugate. In this study, the effectiveness of AN-152 was heightened by receptor up-regulation. The cytotoxic effect of AN-152 can be regulated by the number of active LH-RH receptors on cancer cells. LH-RH receptor-positive (MCF-7) and -negative (UCI-107) cancer cells were treated with epidermal growth factor (EGF) or the somatostatin analogue, RC-160. EGF and RC-160 have been shown previously to regulate LH-RH receptors through phosphorylation. The effect of receptor regulation, by hormone exposure, on the cytotoxicity of AN-152 and doxorubicin and on the cellular uptake of AN-152, [D-Lys6]LH-RH, or doxorubicin was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and by two-photon laser scanning microscopy. The results demonstrated that the cellular entry of the conjugate was: (a) specific for cancers with LH-RH receptors; (b) up-regulated by EGF; (c) down-regulated by RC-160; and (d) the cytotoxicity of the AN-152 paralleled the efficiency of entry. This study illustrates the potential use of receptor regulation for increasing the efficacy of chemotherapeutic approaches that are directed to cell surface receptors.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Membrane; Cell Nucleus; Cytoplasm; Doxorubicin; Drug Carriers; Drug Screening Assays, Antitumor; Drug Synergism; Epidermal Growth Factor; Fluorescent Dyes; Gonadotropin-Releasing Hormone; Humans; Microscopy, Fluorescence; Receptors, LHRH; Somatostatin; Tumor Cells, Cultured
PubMed: 10945629
DOI: No ID Found