Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The author reviewed present status and progress of endocrine nuclear medicine including thyroid, parathyroid, adrenocortical, adrenomedullary and somatostatin receptor imaging and also radionuclide therapy of Basedow's disease, metastatic foci of post-operative thyroid cancer and malignant neural crest tumor. Relatively new imaging agents include 99mTc-MIBI and 99mTc-tetrofosmin for parathyroid imaging and 111In-pentetreotide for somatostatin receptor imaging. It is hoped that therapy of malignant neural crest tumors such as metastatic pheochromocytoma and neuroblastoma with 131I-MIBG and somatostatin receptor imaging will be available in Japan as soon as possible.
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PMID:[Present status and progress of endocrine nuclear medicine]. 1008 59

Somatostatin receptor expression is a favorable prognostic factor in human neuroblastoma. Somatostatin receptors have been demonstrated in vitro by pharmacologic analysis of tumor tissue and in vivo by diagnostic radioreceptor scintigraphy. However, which receptor subtypes (sst(1), sst(2), sst(3), sst(4), and sst(5)) are expressed in these tumors has not yet been delineated. We used RT-PCR to analyze expression of the five somatostatin receptor genes in 32 neuroblastoma tumor specimens. All 32 tumor specimens expressed mRNA for c-abl and sst(1); sst(2) mRNA was detected in 27/32 samples and somatostatin mRNA was detected in 30/32 tumor specimens. The remaining receptor subtypes, sst(3), sst(4), and sst(5) were variably expressed. Receptor protein for sst(1) and sst(2) was visualized in tumor neuroblasts as well as in endothelial cells of tumor vessels using immunostaining with specific anti-receptor antibodies. The effect of high expression of somatostatin receptors on cell proliferation was examined in SKNSH neuroblastoma cells transfected with sst(1) and sst(2). SS(14) binding to wild-type SKNSH cells was undetectable; but the native peptide bound with high affinity to the SKNSH/sst(1) and SKNSH/sst(2) neuroblastoma cell lines. Pharmacologic analysis of binding with two long-acting analogues, CH275 and octreotide, confirmed selective expression of sst(1) and sst(2) in stably transfected SKNSH cells. Formation of neuroblastoma xenograft tumors in nude mice was significantly delayed for both SKNSH/sst(1) (P<0.001) and SKNSH/sst(2) (P<0.05) cells compared to wild-type SKNSH. We conclude that: (1) Somatostatin receptors, sst(1) and sst(2), are expressed in the majority of neuroblastomas at diagnosis; and (2) upregulation of functional sst(1) or sst(2) in neuroblastoma cell lines suppresses tumorigenicity in a xenograft model. These observations suggest that somatostatin receptors may be a useful therapeutic target in neuroblastoma.
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PMID:Somatostatin receptor gene expression in neuroblastoma. 1070 54

Neuroendocrine tumors are characterized by the expression of different peptides and biogenic amines. These rare tumors tend to grow slowly and are notoriously difficult to localize, at least in the early stages. Surgical removal is the only definitive therapeutic option for neuroendocrine tumors and relief from hyperfunctional status. The effectiveness of surgical treatment is invariably dependent upon the complete surgical excision of all tumor tissue, because microscopic and occult disease not readily seen by the surgeon may remain in situ, leading to shortened survival. Therefore, pre- and intraoperative localization of the primary as well as of metastatic tumors is of utmost importance. Radioguided surgery (RGS) is an intraoperative technique that enables the surgeon to localize radiolabelled tissue based on the characteristics of the various tissues. Concerning gastroenteropancreatic tumors (GEP), intraoperative gamma probe examination is able to reveal small tumor sites accumulating (111In-DTPA-D-Phe1)-pentetreotide more efficiently (> 90%) than somatostatin receptor scintigraphy (68%-77%), because lesions with a size smaller than 5 mm in greatest dimension could be identified. Furthermore, RGS identified 57% more lesions when compared to the "palpating finger" of the surgeon. In medullary thyroid cancer (MTC), surgical removal of the tumor is the first and most efficient treatment of the disease. Persistent or increasing serum calcitonin and carcinoembryonic antigen (CEA) levels imply tumor recurrence after thyroid ablation. For imaging recurrent MTC many radiopharmaceuticals have been used to visualize tumor sites, but none of them has shown excellent sensitivity. Preoperative somatostatin receptor scintigraphy and intraoperative RGS in patients with recurrent MTC demonstrate only part of the tumor sites and cannot visualize small tumor sites (less than 10 mm). In comparison, RGS using 99mTc(V)-DMSA detects metastases with a size of 5 mm in diameter, whereas the "palpating finger" of the surgeon localized metastases with a size of more than 1 cm in diameter. In patients with recurrent MTC, intraoperative gamma probe examination is able to localize over 30% more tumor lesions when compared with conventional preoperative imaging modalities and surgical findings. MIBG scintigraphy is the most sensitive technique for the detection and staging of neuroblastoma (sensitivity 92%; specificity nearly 100%). Intraoperative RGS with iodine labelled MIBG has been developed to improve the definition of tumor limits or to localize small, nonpalpable tumors. Comparison of 123I- and 125I-labelled MIBG revealed a sensitivity of 91% and 92%, respectively; the specificity of 125I (85%) was significantly higher than that of 123I (55%). In addition to scintigraphy of the adrenal glands by precusors of adrenal hormones, imaging with a radiolabelled somatostatin analogue is possible; however, (111In-DTPA-D-Phe1)-pentetreotide is not specific for any adrenal disease or function and the relatively high radioligand accumulation in the kidneys limited the use for detection of tumors in the area of the adrenal glands.
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PMID:Intraoperative use of gamma-detecting probes to localize neuroendocrine tumors. 1093 2

Neuroblastoma (NB) is the most common pediatric neuroendocrine tumor, and it is characterized by a quite variable clinical course. We previously found a great variability in the expression of somatostatin receptor type 2 (sst2) in several human NB cell lines and primary tumors. In this report we investigated whether expression of sst2 is somehow related to clinical outcome. We performed a retrospective study on 54 patients with a maximum follow-up of 100 months. The concentration of specific messenger ribonucleic acid (mRNA) for sst2 was measured by competitive RT-PCR and validated, in a small subset of samples, by quantitative imaging of gene (in situ hybridization) and protein (immunohistochemistry) expression. We found that sst2 mRNA was variably expressed in all NB tumors (range, 2.5 x 10(5) to 8 x 10(9) molecules/microg RNA) with a relevant reduction in the more advanced stage (P < 0.01). Analysis of Kaplan-Meier curves indicated that sst2 expression is positively related to the overall (P < 0.0001) and event-free (P < 0.0001) survival. Expression of sst2 was negatively related to tumor stage (P < 0.02) and MYCN amplification (P < 0.001), a poor prognostic factor. However, the prognostic information derived from sst2 is apparently independent from MYCN amplification, as assessed by stratifying sst2 values according to MYCN. In addition, the expression of sst2 was the only significant prognostic factor (P < 0.02) when it was included in a multivariate model containing other well known prognostic factors such as age, stage, and MYCN amplification. Hence, we propose that sst2 expression represents a new prognostic marker for NB. The main clinical value of a quantitative measure of sst2 lies in its ability to detect patients at low risk, independently from other prognostic factor, including MYCN amplification.
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PMID:Quantitative determination of sst2 gene expression in neuroblastoma tumor predicts patient outcome. 1106 51

We reported previously that the expression of type 2 somatostatin receptor (sst2) was positively related to patient outcome in the childhood tumor neuroblastoma. To quantitate the expression of mRNA sst2 expression, we used a competitive RT-PCR assay. To improve the practicability of this measurement and its applicability to large groups of patients, we present here an original 'real-time' quantitative RT-PCR method, based on a dual-labeled fluorogenic probe and the TaqMan technology. By this method, we have measured sst2 mRNA expression in 24 breast cancer samples and 26 colon carcinomas as well as on the corresponding non-adjacent non-neoplastic tissue of the same patients. The proposed method has a dynamic range of 4 x 10(4) to 4 x 10(8) molecules of sst2 mRNA. The intra-assay precision of the test, evaluated as signal detection variability, was 2.4%. Accuracy, evaluated by the addition of standard RNA to unknown samples, provided a mean recovery of 98+/-2%. A significant correlation has been observed in a study performed in 24 neuroblastoma samples measured both with the proposed method and with a competitive RT-PCR assay (r=0.913, p<0.001). In our preliminary clinical study, no significant differences were observed in sst2 mRNA levels between normal and tumor specimens in both colorectal (normal tissue 5.1 x 10(7)+/-2.0 x 10(7) molecules/microg total RNA, cancer tissue 9.7 x 10(7)+/-4.2 x 10(7)) and breast tumors (normal tissue 5.5 x 10(8)+/-2.0 x 10(8), cancer tissue 4.4 x 10(8)+/-3,7 x 10(8)).However, in colorectal cancer, sst2 mRNA values of subjects with high circulating carcinoembryonic antigen (CEA) levels (>5 ng/ml) were statistically lower (2.3 x 10(7)+/-6.2 x 10(6) molecules/, microg total RNA; p<0.05) than those of subjects with low CEA concentration (1.4 x 10(8)+/-6.7 x 10(7)). Also, the sst2 mRNA ratio between normal and tumor tissue (N/T ratio) resulted significantly inversely related to CEA levels. In breast cancer, a significant difference was found between the mean N/T ratio of negative (below 10 fmol/mg protein) and positive estrogen receptor tumors (p<0.05). Analogous results were found selecting breast tumors on the basis of the progesterone receptor status (p<0.05). The proposed method is accurate, precise, sensitive and less labor-intensive than the competitive RT-PCR assay. For a correct evaluation of sst2 mRNA expression, it seems very important to measure the sst2 expression both in tumor and in the non-tumoral non-adjacent tumor specimens.
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PMID:Type-2 somatostatin receptor mRNA levels in breast and colon cancer determined by a quantitative RT-PCR assay based on dual label fluorogenic probe and the TaqMan technology. 1138 68

The cyclic somatostatin (SST) analogue, cyclo-(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr[BZL]) (cSSTA), has been widely used as somatostatin antagonist. In the human neuroblastoma cell line SH-SY5Y the cyclopeptide acts as a somatostatin receptor agonist. Similar to SST, cSSTA inhibits cell proliferation, activates the protein tyrosine phosphatase SHP-2, and stimulates the activity of mitogen-activated protein kinase. These results suggest that in SH-SY5Y neuroblastoma cells somatostatin receptors may exist which exhibit altered antagonist binding properties.
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PMID:The putative somatostatin antagonist, cyclo-(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr[BZL]), may act as potent antiproliferative agonist. 1218 54

Neuroblastoma is a frequent tumor of childhood and remains a leading cause of death despite treatment intensification. Many clinical, biological and genetic factors have been identified and are associated with prognosis and outcome after treatment. Initial staging plays a major role for determining the therapeutic strategy. Radioiodinated metaiodobenzylguanidine (MIBG) scintigraphy is a highly sensitive and specific method for diagnosing, staging and also monitoring response to therapy. In children with high-risk neuroblastoma, relapse may occur any time after remission has been obtained. (123)I-MIBG scintigraphy is a reliable method to follow-up those children and allows early detection of recurrence. As far as outcome is concerned, MIBG scintigraphy has not proven to have any prognostic value. Other radiolabeled tracers, such as pentetreotide, monoclonal antibodies, and sestamibi have been compared with MIBG. Up to now, no method has demonstrated a reliable prognostic value, even though neuroblastoma that express somatostatin receptor seem to have a better clinical outcome and survival rate. Positron emission tomography (PET) with (18)F-fluorodeoxyglucose has been used successfully in staging and monitoring response to treatment of MIBG negative tumors. (11)C-hydroxyephedrine has shown promising results in staging neuroblastoma, but is not as widely available as MIBG. With respect to biological and genetic factors, nuclear medicine procedures play a major role in initial diagnosis and staging of neuroblastoma. At the moment, MIBG scintigraphy is certainly the most sensitive and specific method for initial staging of the disease, as well as monitoring the response to treatment and detecting early relapse.
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PMID:Nuclear medicine procedures and neuroblastoma in childhood. Their value in the diagnosis, staging and assessment of response to therapy. 1271 52

Two CPT-SSA conjugates, JF-10-71 and JF-10-81, containing a chemically adjustable release-rate carbamate linker, have been reported previously by us to potently inhibit growth of human neuroblastoma IMR32 cells overexpressing somatostatin receptor type II (SSTR2) but are stable under buffer incubation conditions or in rat plasma. Further experiments now reveal that the conjugates performed well against many additional cell lines, particularly somatostatin receptor containing rat pancreatic CA20948 cells that were actually more sensitive to the conjugates than free camptothecin itself. JF-10-71 and JF-10-81 also were examined for their inhibitory effects on the growth of this and several other tumors transplanted into rats (CA20948) or nude mice. CA20948 tumors, known to overexpress SSTR2 and grown in Lewis rats, were treated, respectively, with nontoxic 400 nmol/kg intraperitoneal (i.p.) doses of JF-10-71 or JF-10-81. Also, SSTR2-positive human SCLC NCI-H69 tumors transplanted in nude mice were treated in a similar fashion. Human prostate PC-3 tumors, which do not contain high concentrations of SSTR2, also were grown in nude mice and treated with a 400 nmol/kg ip dose of JF-10-71. Both cytotoxic conjugates significantly inhibited growth of SSTR2-specific pancreatic and SCLC tumors, but JF-10-81 did not significantly affect PC-3 tumor growth. These experimental results suggested that CPT-SSA conjugates can effectively target and kill tumor cells growing in vivo and that the effect is mediated by somatostatin receptors resulting in either release of camptothecin at the cell surface or, more likely, after receptor-mediated cellular internalization.
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PMID:Effects of camptothecin conjugated to a somatostatin analog vector on growth of tumor cell lines in culture and related tumors in rodents. 1537 Nov 4

Neuroblastoma is the most common extracranial solid tumor of childhood. It commonly presents in children younger than 2 years of age, with 90% being younger than 5 years of age. There is marked variability in clinical behavior ranging from spontaneous regression or differentiation into benign tumors to rapid and progressive fatal disease. Approximately 50% of patients will have metastases at presentation. The management is dependent on age, stage of disease, and biological and biochemical markers. Nuclear medicine plays an important role in the initial staging, as a prognostic indicator, for assessment of response to treatment, and also in therapy. The most common nuclear medicine diagnostic studies are (99m)Tc-disphosphonate bone scintigraphy and (123)I-MIBG (metaiodobenzylguanidine) scintigraphy. Bone scintigraphy has been the main investigational modality to diagnose skeletal metastases. Whole body imaging with (123)I-MIBG has become the preferred diagnostic test because this agent accumulates in neuroblastoma in 90% to 95% of cases and will accumulate in the primary tumor and metastases particularly in bone, bone marrow, lymph nodes, and soft tissues. MIBG can be used to assess therapy response and is a significant prognostic indicator. Other diagnostic techniques include positron emission tomography (PET)/computed tomography, mainly using (18)F-fluorodeoxyglucose. Other more experimental PET agents, as well as radiolabeled antibodies and octreotide, also are being investigated. Therapy has mainly focused on palliation and has been used alone or in combination with chemotherapy in high-risk refractory or relapsed patients. Major attention is being placed on stratification of patients to try and reduce the side effects associated with intensive megatherapy in the low to intermediate risk patients. Neuroendocrine tumors (NETs) are rare in childhood, but nuclear medicine techniques, mainly using MIBG and somatostatin receptor agents, have a role in diagnosis, staging, and a limited role in therapy. Newer radiopharmaceuticals, including PET agents, are being evaluated for the assessment of NET. Nuclear medicine techniques play a major role in the management of neuroblastoma and NET.
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PMID:Neuroblastoma and other neuroendocrine tumors. 1754 28

Several neuroendocrine tumors are known to express both the somatostatin receptor subtype 2 (SSTR2) and the norepinephrine transporter (NET), and radiopharmaceuticals directed toward both these targets such as MIBG and octreotide derivatives are routinely used in the clinic. To investigate the possibility of targeting both NET and SSTR2 conjointly, a conjugate of radioiodinated MIBG and octreotate was synthesized. Attempts to synthesize the radioiodinated target compound (MIBG-octreotate; [ (131)I] 12a) from a tin precursor were futile; however, it could be accomplished from a bromo precursor by exchange radioiodination in 3-36% ( n = 10) radiochemical yields. The total uptake of [ (131)I] 12a in SK-N-SH human neuroblastoma cells transfected to express SSTR2 (SK-N-SHsst2) was similar to that for [ (125)I]MIBG at all time points (34.9 +/- 2.4% vs 43.8 +/- 1.2% at 4 h; p < 0.05), while it was substantially lower (5.4 +/- 0.3% vs 35.9 +/- 1.2%) in the SH-SY5Y cell line, a subclone of SK-N-SH line that is known to express SSTR2. The NET blocker desipramine reduced the uptake of [ (131)I] 12a only to a small extent, further suggesting a limited role of NET in its binding and accumulation. Uptake of [ (131)I] 12a in SK-N-SHsst2 cells was 8-10-fold higher ( p < 0.05) than that of [ (125)I]I-Gluc-TOCA, an octreotide analogue, at all time points over a 4 h period and was reduced to about 20% by 10 muM octreotide demonstrating that the uptake of [ (131)I] 12a in this cell line is predominantly mediated by SSTR2. The intracellularly trapped radioactivity in SK-N-SHsst2 cells was substantially higher for [ (131)I] 12a compared to that for [ (125)I]OIBG-octreotate, an isomeric congener of 12a. Because MIBG has more specific NET-mediated uptake than OIBG, this suggests at least a partial role for NET-mediated uptake of [ (131)I] 12a in this cell line. While further refinement in the structure of the conjugate-probably interposition of a flexible and/or cleavable linker between the MIBG and octreotate moieties-may be necessary to make it a substrate/ligand for both NET and SSTR2, this conjugate is demonstrated to be much superior than I-Gluc-TOCA with respect to the uptake in SSTR2-expressing cells.
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PMID:A radioiodinated MIBG-octreotate conjugate exhibiting enhanced uptake and retention in SSTR2-expressing tumor cells. 1797 23


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