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PubMed2001

A comparison of targeting of neuroblastoma with mIBG and anti L1-CAM antibody mAb chCE7: therapeutic efficacy in a neuroblastoma xenograft model and imaging of neuroblastoma patients.

Iodine-131 labelled anti L1-CAM antibody mAb chCE7 was compared with the effective neuroblastoma-seeking agent 131I-labelled metaiodobenzylguanidine (MIBG) with regard to (a) its therapeutic efficacy in treating nude mice with neuroblastoma xenografts and (b) its tumour targeting ability in neuroblastoma patients. The SK-N-SH tumour cells used in the mouse experiments show good MIBG uptake and provide a relatively low number of 6,300 binding sites/cell for mAb chCE7. Tumours were treated with single injections of 131I-MIBG (110 MBq) and with 131I-labelled mAb chCE7 (17 MBq) and both agents showed antitumour activity. After therapy with 131I-chCE7, the subcutaneous tumours nearly disappeared; treatment with 131I-MIBG was somewhat less effective, resulting in a 70% reduction in tumour volume. A calculated tumour regrowth delay of 9 days occurred with a radioactivity dose of 17 MBq of an irrelevant control antibody mAb 35, which does not bind to SK-N-SH cells, compared with a regrowth delay of 34 days with 131I-mAb chCE7 and of 24 days with 131I-MIBG. General toxicity appeared to be mild, as assessed by a transient, approximate 10% maximum decrease in body weight during the treatments. The superior growth inhibition achieved by 131I-chCE7 compared with 131I-MIBG can be explained by its prolonged retention in the tumours, due to slower normal tissue and plasma clearance. Cross-reaction of mAb chCE7 with L1-CAM present in normal human tissues was investigated by direct binding of radioiodinated mAb to frozen tissue sections. Results showed a strong reaction with normal human brain tissue and weak but detectable binding to normal adult kidney sections. Seven patients with recurrent neuroblastoma were sequentially imaged with 131I-MIBG and 131I-chCE7. The results underlined the heterogeneity of neuroblastoma and showed the two imaging modalities to be complementary. 131I-chCE7 scintigraphy may have clinical utility in detecting metastases which do not accumulate 131I-MIBG, and the antibody may hold potential for radioimmunotherapy, either by itself or in combination with 131I-MIBG.

3-Iodobenzylguanidine↗

PubMed2006

Prognostic value of the International Neuroblastoma Pathology Classification in Neuroblastoma (Schwannian stroma-poor) and comparison with other prognostic factors: a study of 182 cases from the Spanish Neuroblastoma Registry.

In addition to clinical and biological factors, further valuable prognostic information in neuroblastoma (Schwannian stroma-poor) (NB) patients is provided by the histopathologic analysis and the application of the International Neuroblastoma Pathology Classification (INPC) system. The objective of this study was to assess the prognostic impact of the INPC classification in a series of NB (Schwannian stroma-poor) and its relation with other prognostic factors. One hundred eighty-two cases of NB were collected from the files of the Spanish Neuroblastoma Registry. Slides were reviewed, and NB cases were grouped into favorable and unfavorable categories according to INPC criteria, taking into account morphological features (mitosis-karyorrhexis index, histological subtype) and patient's age at diagnosis. Other pathological [presence of calcifications, tissular components, and number of mitotic cells per 10 high-power field (HPF)], immunohistochemical (P-glycoprotein and Ki-67 protein expression) and genetic (MYCN amplification and chromosome 1p deletion) features were also studied. Statistical analyses of overall survival with Kaplan-Meier curves and a multivariate study using Cox regression were performed (40.3% of NBs were considered favorable and 59.7% unfavorable). Unfavorable NB showed a mean survival time of 57 months compared with 89 months in favorable cases. Advanced stage, more than ten mitoses per 10 HPF, Ki-67 expression in more than 30% of tumor cells, MYCN oncogene amplification and chromosome 1p deletion were observed more frequently in unfavorable NB. The Cox regression analysis demonstrated that clinical stage (International Neuroblastoma Staging System stage 4) and histological subtype (undifferentiated NB) were the most important factors that influence the overall survival (p<0.001). INPC classification results are major prognostic indicators in NB and should be considered in the therapeutic stratification of NB patients.

Child↗

PubMed2006

Is there a benefit of 131 I-MIBG therapy in the treatment of children with stage 4 neuroblastoma? A retrospective evaluation of The German Neuroblastoma Trial NB97 and implications for The German Neuroblastoma Trial NB2004.

AIM: (131)I-meta-iodobenzylguanidine ((131)I-MIBG) therapy has been used in neuroblastoma treatment for many years but its value in high intensive first line treatment protocols is not exactly known. PATIENTS, METHODS: Stage 4 neuroblastoma patients >1 year with (123)I-MIBG positive residual disease (primary tumour and/or metastasis) after complete induction chemotherapy according to the German neuroblastoma trial NB97 were retrospectively analyzed. RESULTS: One-hundred-eleven patients had (123)I-MIBG positive residual disease after complete induction chemotherapy. Forty patients received (131)I-MIBG therapy using a median activity of 0.44 GBq/kg body weight. By univariate analysis, patients who underwent (131)I-MIBG therapy had a better 3-year event free survival (3-y-EFS 46 +/- 8%) and 3-year overall survival (3-y-OS 58 +/- 9%) than 71 patients without (131)I-MIBG therapy (3-y-EFS 19 +/- 5%, p = 0.003; 3-y-OS 43 +/- 6%, p = 0.037). However, subgroup analysis of 66 patients who underwent high dose chemotherapy with autologous stem cell transplantation (ASCT) during treatment found a very similar outcome with (131)I-MIBG therapy (3-y-EFS 49 +/- 9%, 3-y-OS 59 +/- 10%) and without (131)I-MIBG therapy (3-y-EFS 33 +/- 9%, p = 0.171; 3-y-OS 59 +/- 9%, p = 0.285) due to the dominating effect of ASCT. By multivariate analysis, (131)I-MIBG therapy had no impact on EFS (p = 0.494) and OS (p = 0.891). Only ASCT, external beam radiation therapy and MYCN amplification were important for EFS and OS. CONCLUSIONS: An independent advantage of I-131-MIBG therapy could not be proven in this retrospective analysis. The ongoing German Neuroblastoma Trial NB2004 will address the influence of (131)I-MIBG therapy with emphasis on tumour dosimetry.

3-Iodobenzylguanidine↗

PubMed1994

Neuroblastomas of the central nervous system--clinicopathological features of a cerebellar neuroblastoma in comparison with a metastatic cerebral neuroblastoma.

Two patients with neuroblastoma of the central nervous system are described. The first, a 10-month-old male infant with symptoms of vomiting and weakness of the right upper extremity, was found on magnetic resonance imaging (MRI) to have enhanced mass lesion in the left hemisphere, vermis of the cerebellum and part of brain stem. The second, a 3-year-old boy who had swelling of the right side of the head, was found on computed tomography (CT) to have enhanced mass lesion of the frontal hemisphere and frontal bone. Histological examination of the surgical specimen of both cases demonstrated neuronal differentiation. The clinicopathological features of cerebellar neuroblastoma in comparison with metastatic neuroblastoma of the frontal lobe were discussed.

Brain Neoplasms↗

PubMed1993

Distinct cytotoxicity against neuroblastoma cells of peripheral blood and tumor-infiltrating lymphocytes from patients with neuroblastoma.

The cytotoxicity against neuroblastoma cells of IL-2-activated peripheral blood (PBL) and tumor-infiltrating lymphocytes (TIL) was evaluated in seventeen patients with neuroblastoma. Regional lymph node lymphocytes (LNL) were similarly studied in some patients. Three allogeneic neuroblastoma cell lines, LA2D2, LA2B4 and SIFA, established from the different metastases of the same patient were used as targets. Of the three neuroblastoma lines, LA2D2, with low CD56 expression, was the most susceptible to IL-2-activated lymphocytes, while SIFA, with high CD56 expression, was resistant in the greatest degree. LA2B4 showed moderate susceptibility. Although TIL (73.9 +/- 2.1%), LNL (81.0%) and PBL (76.2 +/- 3.1%) revealed similar cytotoxic activity to K562, they demonstrated distinct cytotoxic activities to each neuroblastoma cell line, as follows: against LA2D2: TIL 56.3 +/- 4.2%, LNL 52.1%, PBL 33.6 +/- 4.9% (P < 0.01); against LA2B4: TIL 47.3 +/- 3.3%, LNL 37.8%, PBL 33.7 +/- 4.8% (P < 0.05); against SIFA: TIL 27.0 +/- 6.2%, LNL 20.7%, PBL 13.9 +/- 2.4% (P = 0.056). TIL always showed higher cytotoxic activity against neuroblastoma cells than those of LNL and PBL, whereas LNL were more cytotoxic than PBL. This data showed that TIL from neuroblastoma patients preferentially killed neuroblastoma cells. It was suggested that lymphocytes in the tumor site and regional lymph node could have been sensitized with neuroblastoma-related antigens and exert preferential killing activity against neuroblastoma cells. Phenotypical analysis revealed that TIL had a larger population of CD56+ cells than PBL. Conversely, PBL had a higher population of CD16+ cells than TIL. The cytotoxic activity of TIL significantly decreased by the depletion of CD56+ cells (10.9 +/- 6.2 from 49.9 +/- 5.9% against LA2D2, P < 0.001). These results indicated that CD56+ cells were most responsible for the killing of neuroblastoma cells, and that TIL, with a high proportion of CD56+ cells with strong activity, would be the best source for the immunotherapy of neuroblastoma. Additionally, since neuroblastoma cell lines used in the present study were derived from the different metastases of the same patient, heterogeneity in the susceptibility to lymphocytes might result from the differential expression of tumor-related antigens on these cell lines.

Antigens, Neoplasm↗

PubMed2004

Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice.

BACKGROUND: The prognosis of neuroblastoma patients remains unsatisfactory. Therefore, developing an effective treatment strategy is important. Resveratrol, a natural polyphenol, possesses chemopreventive and antitumor effects. We investigated the effects of resveratrol on the proliferation, apoptosis, and cell cycle alteration of neuroblastoma cells and determined its effects on neuroblastoma tumors in mice. METHODS: Cytotoxic effects, cellular apoptosis, and alterations in the cell cycle were determined in neuro-2a neuroblastoma cells exposed for varying lengths of time to a series of resveratrol concentrations. Expression of associated cell cycle regulatory proteins, cyclin E and p21, was detected by Western blot analysis, and the antitumor effects of resveratrol were investigated by treating subcutaneous neuroblastoma tumors with intraperitoneal injections of 40 mg/kg resveratrol daily for 28 days. RESULTS: Resveratrol exerted cytotoxic effects on neuroblastoma cells. After resveratrol treatment, the apoptosis rate of the neuroblastoma cells significantly increased, a significant accumulation of cells occurred at the S phase of the cell cycle, p21 was downregulated, and cyclin E was upregulated. In addition, resveratrol treatment suppressed the growth rate of subcutaneous neuroblastomas, resulting in 70% long-term survival. CONCLUSION: Resveratrol caused significant cytotoxicity and increased apoptosis and S-phase accumulation of neuroblastoma cells. S-phase accumulation was related to the down-regulation of p21 and up-regulation of cyclin E. In addition, resveratrol exerted antitumor effects on neuroblastomas in mice. Thus, resveratrol shows promise for the treatment of neuroblastoma.

Animals↗

PubMed2000

Angiogenesis and neuroblastomas: interleukin-8 and interleukin-8 receptor expression in human neuroblastoma.

PURPOSE: Studies have demonstrated that the pro-angiogenic cytokine interleukin-8 (IL-8) and the IL-8 receptors likely have a role in the growth and metastasis of various solid tumors. We hypothesized that in vivo neuroblastoma expresses IL-8 and the IL-8 receptors A and B, and that factors known to regulate IL-8 expression are present and active in the neuroblastoma microenvironment. MATERIALS AND METHODS: To confirm the presence of IL-8/IL-8 receptors in neuroblastoma, immunohistochemical analysis for IL-8 and its receptors was performed on 10 archival specimens, including benign adrenal and well to poorly differentiated neuroblastoma samples. Immunohistochemical analysis was also performed for interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha. Cultured neuroblastoma cells SK-N-MC and SK-N-SH were stimulated with 10 ng./ml. IL-1beta or tumor necrosis factor-alpha and control media (15 each). Cell culture supernatants were analyzed with enzyme-linked immunosorbant assay for IL-8 levels at 24 and 48 hours. RESULTS: Minimal expression of IL-8 was noted in benign adrenal tissue but expression for IL-8 was present in all neuroblastoma specimens. Microvessel staining was present in 30% of the specimens. All tumor specimens expressed IL-8 receptor B, and both receptors were expressed in the tumor microvasculature. Immunohistochemical analysis confirmed the presence of IL-1beta and tumor necrosis factor in the neuroblastoma microenvironment. In vitro studies demonstrated that SK-N-MC and SK-N-SH cells express low levels of IL-8 under normal conditions and that IL-1beta and tumor necrosis factor-alpha significantly increased expression of IL-8 at 24 and 48 hours. CONCLUSIONS: Our results indicate that IL-8 and its receptors are expressed in neuroblastoma tumor specimens. In addition, the fact that IL-1beta and tumor necrosis factor-alpha are expressed in the neuroblastoma microenvironment combined with our in vitro results suggests that these cytokines may be involved in in vivo regulation of IL-8 in human neuroblastoma. Understanding the angiogenic factors and regulatory cascade promoting angiogensis in neuroblastoma may lead to the development of effective anti-angiogenic strategies.

Enzyme-Linked Immunosorbent Assay↗

PubMed2005

Shc family expression in neuroblastoma: high expression of shcC is associated with a poor prognosis in advanced neuroblastoma.

The biological features and prognosis of neuroblastoma, a neural crest-derived pediatric tumor, are closely associated with expression of the Trk receptor. Because the Shc family proteins (ShcA, ShcB, and ShcC) are adaptors for various receptors, including Trk receptors, and are regulators of neuronal cell development, we speculated that they may play a role in neuroblastoma. Therefore, in this study, we used semiquantitative reverse transcription-PCR to examine the expression of these three genes in 15 neuroblastoma cell lines, an all-trans-retinoic acid-treated neuroblastoma cell line, and 52 tumor samples. In neuroblastoma cell lines and tumor samples, shcA was ubiquitously and highly expressed. Little expression of shcA was observed. Also, shcB was hardly expressed in neuroblastoma cell lines, but its expression in RT-BM-1 cells was enhanced after all-trans-retinoic acid-induced differentiation, and it was highly expressed in low-stage tumors (P = 0.0095). This suggests that ShcB participates in cellular differentiation and may correlate with a favorable prognosis in neuroblastoma. Finally, the expression of shcC was observed in most of the neuroblastoma cell lines and in some stage 4 patients. Patients with a high expression of shcC had a very poor prognosis (P < 0.0001) and amplification of MYCN, and all died within 31 months after diagnosis. Therefore, ShcC seems to be associated with an aggressive tumor phenotype, perhaps by enhancing TrkB signals. Our results suggest that the expressions of shcB and shcC are important biological factors in neuroblastoma and are useful prognostic indicators.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Human fetal neuroblast and neuroblastoma transcriptome analysis confirms neuroblast origin and highlights neuroblastoma candidate genes.

BACKGROUND: Neuroblastoma tumor cells are assumed to originate from primitive neuroblasts giving rise to the sympathetic nervous system. Because these precursor cells are not detectable in postnatal life, their transcription profile has remained inaccessible for comparative data mining strategies in neuroblastoma. This study provides the first genome-wide mRNA expression profile of these human fetal sympathetic neuroblasts. To this purpose, small islets of normal neuroblasts were isolated by laser microdissection from human fetal adrenal glands. RESULTS: Expression of catecholamine metabolism genes, and neuronal and neuroendocrine markers in the neuroblasts indicated that the proper cells were microdissected. The similarities in expression profile between normal neuroblasts and malignant neuroblastomas provided strong evidence for the neuroblast origin hypothesis of neuroblastoma. Next, supervised feature selection was used to identify the genes that are differentially expressed in normal neuroblasts versus neuroblastoma tumors. This approach efficiently sifted out genes previously reported in neuroblastoma expression profiling studies; most importantly, it also highlighted a series of genes and pathways previously not mentioned in neuroblastoma biology but that were assumed to be involved in neuroblastoma pathogenesis. CONCLUSION: This unique dataset adds power to ongoing and future gene expression studies in neuroblastoma and will facilitate the identification of molecular targets for novel therapies. In addition, this neuroblast transcriptome resource could prove useful for the further study of human sympathoadrenal biogenesis.

Databases, Genetic↗

PubMed2004

Large cell neuroblastoma: a distinct phenotype of neuroblastoma with aggressive clinical behavior.

BACKGROUND: Among cases of undifferentiated and poorly differentiated tumors in the neuroblastoma (Schwannian stroma-poor) category, the authors histologically identified a group of rare tumors, known as large cell neuroblastomas (LCNs), that are composed of large cells with sharply outlined nuclear membranes and 1-4 prominent nucleoli. METHODS: Histologic and immunohistochemical features of LCN were characterized. Morphologic characteristics, clinical features, and MYCN status were compared between LCNs and conventional neuroblastomas documented in the files of two European centers (the Sir James Spence Institute of Child Health, Royal Victoria Infirmary, University of Newcastle, Newcastle upon Tyne, United Kingdom, and the Medical and Health Sciences Center, University of Pécs, Pécs, Hungary). RESULTS: Of 92 peripheral neuroblastic tumors (pNTs; including neuroblastoma [n = 81]; ganglioneuroblastoma, intermixed [n = 6]; and ganglioneuroblastoma, nodular [n = 5]), 7 (7.6%) qualified as LCN. All 7 LCNs were classified as having unfavorable histology (UH) according to the International Neuroblastoma Pathology Classification. The LCNs were composed of monomorphous undifferentiated neuroblasts and shared certain histologic features, such as a high incidence of high mitosis-karyorrhexis index and a low incidence of calcification, with other neuroblastomas in the conventional UH (c-UH) group. These features were significantly different from those of neuroblastomas in the conventional favorable histology (c-FH) group. On immunohistochemical analysis, LCN tumor cells were positive for neuron-specific enolase (5 of 5 cases), protein gene product 9.5 (5 of 5 cases), synaptophysin (5 of 5 cases), tyrosine hydroxylase (focally in 3 of 3 cases), and NB84 (3 of 5 cases) and negative for CD99. Patients with LCN and patients with c-UH disease had similar clinical features (diagnosis at age > 1 year, often with distant metastasis). The clinical features of these patients also were significantly different from those of patients with c-FH disease. Further analysis demonstrated that the LCN group was significantly different from both the c-UH and c-FH groups with respect to MYCN status (MYCN amplification, 4 of 5 vs. 3 of 17 vs. 8 of 17, respectively; P = 0.023) and survival rate (4-year expected survival, 0% vs. 71% vs. 17%, respectively; P < 0.01). CONCLUSIONS: Because of its unique clinicopathologic features, the authors propose that LCN be recognized as a distinct entity within the undifferentiated and poorly differentiated subtypes of the neuroblastoma category.

Child↗

PubMed2007

Neuroblastoma-derived secretory protein messenger RNA levels correlate with high-risk neuroblastoma.

BACKGROUND/PURPOSE: In advanced-stage neuroblastoma, bulky disease and systemic dissemination can be controlled with intense surgical and medical therapies; however, recurrence rates are very high in this group indicating that residual disease is rarely eradicated. The need to detect residual disease and predict prognosis is critical to planning appropriate treatment regimens for these patients. Recently, neuroblastoma-derived secretory protein (NDSP) was identified and cloned from neuroblastoma. METHODS: Using quantitative real-time PCR, we tested NDSP messenger RNA (mRNA) expression in 45 neuroblastoma tumor samples and 5 bone marrow samples. Correlation between NDSP expression and age at diagnosis, International Neuroblastoma Staging System, MYCN amplification, and Children's Oncology Group risk stratification was analyzed using Spearman nonparametric correlation. RESULTS: Neuroblastoma tissue samples show much higher NDSP mRNA levels above control in 43 of 45 samples (96%); moreover, these levels correlate with the Children's Oncology Group neuroblastoma risk group assignment. We also found that bone marrow samples with known tumor infiltration had much higher NDSP mRNA levels than bone marrow from patients without metastasis. CONCLUSION: From these data, we conclude that NDSP mRNA levels in neuroblastoma tumor tissue correlate with risk group assignment and may serve as a marker for metastasis in bone marrow.

Adult↗

PubMed1997

Analysis of 1;17 translocation breakpoints in neuroblastoma: implications for mapping of neuroblastoma genes.

Deletions and translocations resulting in loss of distal 1p-material are known to occur frequently in advanced neuroblastomas. Fluorescence in situ hybridisation (FISH) showed that 17q was most frequently involved in chromosome 1p translocations. A review of the literature shows that 10 of 27 cell lines carry 1;17 translocations. Similar translocations were also observed in primary tumours. Together with the occurrence of a constitutional 1;17 translocation in a neuroblastoma patient, these observations suggest a particular role for these chromosome re-arrangements in the development of neuroblastoma. Apart from the loss of distal 1p-material, these translocations invariably lead to extra copies of 17q. This also suggested a possible role for genes on 17q in neuroblastoma tumorigenesis. Further support for this hypothesis comes from the observation that in those cell lines without 1;17 translocations, other chromosome 17q translocations were present. These too lead to extra chromosome 17q material. Molecular analysis of 1;17 translocation breakpoints revealed breakpoint heterogeneity both on 1p and 17q, which suggests the involvement of more than 2 single genes on 1p and 17q. The localisation of the different 1p-breakpoints occurring in 1;17 translocations in neuroblastoma are discussed with respect to the recently identified candidate tumor suppressor regions and genes on 1p. In this study, we focused on the molecular analysis of the 17q breakpoints in 1;17 translocations. Detailed physical mapping of the constitutional 17q breakpoint allowed for the construction of a YAC contig covering the breakpoint. Furthermore, a refined position was determined for a number of 17q breakpoints of 1;17 translocations found in neuroblastoma cell lines. The most distal 17q breakpoint was identified in cell line UHG-NP and mapped telomeric to cosmid cCI17-1049 (17q21). This suggests that genes involved in a dosage-dependent manner in the development of neuroblastoma map in the distal segment 17q22-qter. Future studies aim at the molecular cloning of 1;17 translocation breakpoints and at deciphering the mechanisms leading to 1;17 translocations and possibly to the identification of neuroblastoma genes at or in the vicinity of these breakpoints.

Chromosome Mapping↗

PubMed1985

Differential amplification, assembly, and relocation of multiple DNA sequences in human neuroblastomas and neuroblastoma cell lines.

DNA amplification, manifested by homogeneously staining regions in chromosomes and by extrachromosomal, double minute bodies, is characteristic of many neuroblastoma cell lines. Sequences recruited from a specific domain on the short arm of chromosome 2 (2p) are amplified in advanced-stage primary neuroblastomas, whereas sequences from distinctly different regions of 2p are amplified in the neuroblastoma cell line IMR-32. Five different DNA segments, which include the oncogene N-myc, three other fragments derived from the homogeneously staining region of the neuroblastoma cell line IMR-32, and a fifth fragment, derived from the neuroblastoma cell line NB-9, showed differential and variable amplification in 24 advanced-stage neuroblastoma tumors out of 112 tested specimens. All five fragments were mapped within the chromosomal region 2p23-2p25 by three different approaches. However, eight other fragments cloned from the homogeneously staining region of IMR-32 cells, which were not amplified in the tumor tissues examined, were mapped to two more proximal domains of 2p, thousands of kilobases apart from each other and from the chromosomal domain that is amplified in the tumors. These results establish the amplification, to different degrees, of a variable-sized segment of one domain near the terminus of 2p in advanced neuroblastomas. These tumors might ultimately be distinguished according to the pattern of amplification of DNA segments within this domain. The data presented also indicate the existence of a new and complex amplification mechanism in at least one neuroblastoma cell line (IMR-32), which involves not only relocation of DNA from specific genomic domains but also the formation of novel units by splicing together very distant DNA segments.

Base Sequence↗

PubMed1984

[Differentiation induction and potentiation of chemotherapy by PGE1 infusion in patients with neuroblastoma--effect of PGE1 on metastatic potential of neuroblastoma].

Combination of dibutyryl adenosine 3', 5'-cyclic monophosphate or prostaglandin E1 (PGE1) and papaverine effectively induced differentiation of neuroblastoma in mice. Two cases of human neuroblastoma with stage III and IV were administered intraaortic PGE1 infusion combined with oral papaverine and conventional chemotherapy. There were no noticeable side effects and the treatment was effective in decreasing tumor size and promoting tumor maturation in the infused area. However, distant osseous metastases were developed in both cases, during and after the PGE1 administration. They survived 30 and 17 months, respectively, from the initiation of therapy. (Jpn J Cancer Chemother 10(9): 1936-1943, 1983) These results prompted us to study the metastatic potentials of neuroblastoma. In vitro studies demonstrated that cultured human neuroblastoma cells (NB-1, GOTO, SK-N-DZ, SJ-N-KP, SJ-N-CG and SK-N-FI) aggregate human platelets with maximum aggregation ranging from 28% to 51%. Addition of PGE1 or PGD2 to PRP effectively inhibited the tumor-cell-platelet interaction, with IC50 approximately 100 nM for PGE1 and 10 nM for PGD2, respectively. In addition, 50 microM PGE1 or PGD2, 5 microM PGI2 reversed neuroblastoma-induced platelet aggregation in 4 out of 5 cell lines were studied. These findings indicate a the possible role of PGs in effective inhibition of neuroblastoma metastases in vivo. However, two cell lines (SK-N-DZ and SJ-N-CG), which had been exposed to 8.5 microM PGE1 or PGD2 for 90 min and 72 hr, respectively, retained the platelet aggregating activity which was not significantly different from that of untreated cells. We conclude that clinical application of intraaortic PGE1 in the treatment of advanced neuroblastoma has advantage in potentiation of tumor cell kill and in inducing maturation. Administered PGE1 may exert its action in two ways: in preventing tumor metastasis or possibly in enhancing the metastatic potential of neuroblastoma cells. Further refinement of these modalities including other PGs such as PGD2 or PGI2 and more detailed studies on optimal PG administration to prevent metastasis should be evaluated in future.

Alprostadil↗

PubMed1995

Properties of delta opioid receptor in neuroblastoma NS20Y: receptor activation and neuroblastoma proliferation.

Neuroblastoma NS20Y cells possess a high density of stereoselective delta opioid receptors as determined by competition binding with 3H-diprenorphine and various opioid ligands. Scatchard analysis of [3H]diprenorphine saturation binding data revealed a Kd = 0.79 +/- 0.17 nM and Bmax = 370 +/- 50 fmol/mg protein. These opioid binding sites have highest affinity for delta opioid receptor selective agonists and lowest affinity for mu opioid receptor selective agonists. Agonist binding was sensitive to the presence of the monovalent cation, Na+. Activation of receptor with D-Ala2, D-Leu5-enkephalin (DADLE) resulted in dose-dependent inhibition of forskolin-stimulated intracellular [3H]cAMP accumulation, which was antagonized by (-)-naloxone but not (+)-naloxone. Relative potencies of various opioid agonists to inhibit intracellular cAMP production paralleled those observed in neuroblastoma x glioma NG108-15 hybrid cells. Pretreatment of NS20Y cells with pertussis toxin (PTX) eliminated opioid agonist inhibition of adenylyl cyclase activity. Chronic DADLE treatment resulted in desensitization and down-regulation of opioid receptor. An increase in intracellular [3H]cAMP level above the control was observed in the presence of naloxone after chronic DADLE treatment. Therefore, opioid binding sites in neuroblastoma NS20Y cells possess properties of the classical delta opioid receptor type. After neuroblastoma NS20Y was growth arrested by culturing the cells in serum-free medium for 72 hr, proliferation was reinitiated by addition of fetal calf serum (FCS), 0.01% to 12%, and was monitored by either [3H]thymidine incorporation or by dye viability assay. It was demonstrated that naloxone and naltriben but not Met5-enkephalin could attenuate FCS-induced proliferation in a dose-dependent manner. Naltriben was 54-fold more potent than naloxone to attenuate NS20Y proliferation. The maximal level of viable cells per well was reduced (35.2 +/- 1.9%) with no alteration in FCS concentration-dependent stimulation of growth. Similar inhibition by naloxone (37.3 +/- 2.7%) was observed with [3H]thymidine incorporation studies. This naloxone effect was serum concentration-dependent and could be blocked by culturing NS20Y cells in the presence of both naloxone and Met5-enkephalin. Although pretreatment of NS20Y cells with pertussis toxin could attenuate FCS-stimulated proliferation, naloxone effect on growth was not affected by pertussis toxin pretreatment. Furthermore, the naloxone effect was not NS20Y specific. A similar naloxone effect was observed with neuroblastoma N1E115, although not with neuroblastoma x glioma NG108-15, nor human neuroblastoma SHSY5Y, cell lines that have been reported to contain delta opioid receptors. Therefore, activation of delta opioid receptor could modulate FCS-induced growth in some but not all neuroblastoma cell lines.

Adenylate Cyclase Toxin↗

PubMed1994

Intraventricular cerebral neuroblastoma. Analysis of subtypes and comparison with hemispheric neuroblastoma.

Two cases of intraventricular neuroblastomas were compared with cases of intraventricular and hemispheric neuroblastomas that have been reported in the published literature. The following order of tumor subtypes was found in patients with increasing age: hemispheric neuroblastoma, intraventricular undifferentiated neuroblastoma, intraventricular differentiated neuroblastoma, and intraventricular neurocytoma; for patients with intraventricular neuroblastomas, this was also the order of increasing cellular maturation and survival. Neuronal morphologic or epitope differentiation was associated with a longer survival time than lack of differentiation by Kaplan-Meier product-limit estimates and with a better survival rate (chi 2) for intraventricular tumors but not for hemispheric tumors. Pathologic distinction of a neurocytoma was confirmed with immunostaining or ultrastructural studies that suggested that a neurocytoma is a matured neuroblastoma of a granule-cell (interneuron) phenotype. Differences among neuroblastoma groups bolster previous suggestions that intraventricular tumors arise differently than do cases of hemispheric tumors and follow a more benign course when neuronal differentiation is present.

Adult↗

PubMed2003

The synthetic retinoid RO 13-6307 induces neuroblastoma differentiation in vitro and inhibits neuroblastoma tumour growth in vivo.

Retinoids modulate cell proliferation, differentiation and apoptosis in a variety of tumour cells including leukaemia and neuroblastoma, a childhood tumour of the sympathetic nervous system. 13-cis retinoic acid is in clinical use against minimal residual disease in neuroblastoma, where the effect seems to depend on dose, scheduling and tumour mass. Novel retinoids are searched for, to improve potency and lower toxicity. We investigated the effect of the synthetic retinoid Ro 13-6307 on neuroblastoma growth in vitro on SK-N-BE(2) and SH-SY5Y cells. Furthermore, effects on tumour growth and the toxicity profile were investigated in a rat xenograft model. Effects of Ro 13-6307 were compared to 13-cis RA (retinoic acid) in vitro and in vivo. Neuroblastoma cells treated with 1 microM Ro 13-6307 exhibited neuronal differentiation, decreased proliferation and accumulation of cells in G1 phase in at least the same magnitude as 5 microM 13-cis RA. No apoptosis was detected in vitro. Treatment of nude rats with neuroblastoma using Ro 13-6307, 0.12 mg p.o. daily, decreased neuroblastoma growth in vivo, in terms of tumour volume during treatment and tumour weight at sacrifice (p < 0.05). In contrast, Ro 13-6307, 0.08 mg p.o. daily, resulted in no significant reduction in tumour growth. All rats treated with Ro 13-6307 gained less weight than control rats, but they exhibited no other signs of toxicity. The toxicity profile of Ro 13-6307 was similar to what we found with 13-cis RA. Our preclinical results suggest that Ro 13-6307 may be a candidate retinoid for clinical oral therapy of neuroblastoma in children.

Animals↗

PubMed1992

High levels of Mn-superoxide dismutase in serum of patients with neuroblastoma and in human neuroblastoma cell lines.

Levels of serum manganese superoxide dismutase (Mn-SOD) in normal children aged from 1 to 14 years and children with various hematological and malignant diseases were determined by enzyme-linked immunosorbent assay (ELISA). In the normal children, the serum Mn-SOD levels gradually increased in proportion to age. By 8 years of age, the Mn-SOD level was nearly at the adult level. The normal values of serum Mn-SOD (mean +/- SD) of children below 4 and above 8 years old were 48 +/- 10.2 ng/ml and 84 +/- 22.5 ng/ml, respectively. Assuming the upper limit of normal Mn-SOD level in serum to be the mean value +/- 2 SD of children at each age, high serum levels of Mn-SOD were found for 8 of 12 patients with neuroblastoma, three of four patients with Wilms tumor, and four of five patients with acute myeloid leukemia. The patients with neuroblastoma exhibited a transient increase in Mn-SOD following chemotherapy, but after 1 week the levels decreased markedly to the control levels. The changes in serum Mn-SOD levels in the patients with neuroblastoma correlated well with the levels of neuron-specific enolase. Mn-SOD was intensely stained in bone marrow cells of patients whose cancer cells had moved into the bone marrow. High levels of Mn-SOD were also found in cultured human neuroblastoma cells. These data indicate that Mn-SOD is expressed in neuroblastoma cells, may serve as one of the diagnostic and prognostic markers for the neuroblastoma, and may be useful to predict the effectiveness of chemotherapy for neuroblastoma and the recurrence of this disease.

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