Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

This paper presents findings from uptake studies to evaluate the ability of an "artificial lymphatic system" (ALS) to enhance large and small molecular weight drug transport into solid tumors and the therapeutic effect of the additional drug on their growth. These studies also served to test the effectiveness of an implantable multidrain ALS. Walker 256, Neuroblastoma, and Sarcoma dual-tumor models were used to evaluate the effect of ALS aspiration on the uptake of 3F8 monoclonal antibody, and doxorubicin. A tumor shrinkage experiment using Walker 256 dual tumors was used to evaluate the efficacy of an implantable ALS with cyclophosphamide chemotherapy. Drug uptake significantly increased in all aspirated tumors; 3F8 uptake was enhanced 37.4% in the Walker and 93.1% in the Neuroblastoma tumor lines (p<0.05). Doxorubicin uptake increased 23.2% in Sarcoma tumor (p<0.05). The shrinkage study demonstrated that one-drain aspirated tumors shrank 90% faster (p<0.01) than control tumors, while three-drain aspirated tumors shrank 123% faster than control tumors (p<0.01).
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PMID:Enhancing the uptake of chemotherapeutic drugs into tumors using an "artificial lymphatic system". 1092 53

Phosphorylated tau protein is the major component of paired helical filaments in Alzheimer disease (AD). We have previously shown that abnormal tau phosphorylation was induced in neuroblastoma SK-N-SH cells by the anticancer drug, paclitaxel, during apoptosis [Guise et al., 1999: Apoptosis 4:47-58]. In the present study, we first demonstrated a shift from fetal tau to hyperphosphorylated tau after incubation with paclitaxel, that showed some similarities with the hyperphosphorylated tau in AD, by using several tau antibodies, N-Term, Tau-1 and AT-8. Tau phosphorylation occurred independently of caspase-3 activation. We next showed that a sustained activation of ERK (extracellular signal-regulated kinase) induced both tau phosphorylation and apoptosis during paclitaxel treatment (1 microM). The inhibition of ERK activation by using the pharmacological MEK1/2 inhibitor, PD98059 (50 microM), or an antisense strategy, reduced tau phosphorylation and neuronal apoptosis (P < 0.001), indicating a link between ERK activation, tau phosphorylation and apoptosis. Doxorubicin (0.2 microM), an anticancer drug whose mechanism of action is independent of microtubules, also induced ERK activation, tau phosphorylation and apoptosis. Moreover, doxorubicin induced some morphological features of neurodegeneration such as loss of neurites and disorganization of the cytoskeleton in apoptotic neuroblastoma cells. Altogether, our results suggest that tau phosphorylation plays a significant role in apoptosis enhancing disruption of microtubules that in turn leads to formation of apoptotic bodies, suggesting that neurodegeneration and apoptosis are related.
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PMID:Hyperphosphorylation of tau is mediated by ERK activation during anticancer drug-induced apoptosis in neuroblastoma cells. 1117 Jan 75

Primitive neuroectodermal tumors (PNET) are rare malignancies of presumed neural crest origin, most often presenting as bone or soft tissue masses in the trunk or axial skeleton, in children and young adults. Treatment of advanced PNET in adults is not clearly defined in the literature. Data concerning dose-intensive chemotherapy regimens for poor-risk patients with those tumors are sparse, due to rarity of PNET in adults, their diverse presentation, the variable treatment procedures applied and the absence of direct comparisons. On the other hand, the role of anthracyclines in the treatment of advanced soft tissue sarcomas is well known and substantial. Six advanced PNET patients were treated at the Institute for Oncology and Radiology of Serbia, during last five years, with high-doses of doxorubicin or epidoxorubicin combined with cisplatin. The paper reviews each of our patients, discussing how does chemotherapy influence the outcome in these patients, in context of the feasibility of high-doses of anthracyclines in advanced settings. High dose anthracyclines (epidoxorubicin 150 mg/m2) in combination with cisplatin 120 mg/m2 induced a complete response lasting for 63+ months in a patient with desmoplastic medulloblastoma of the cerebellum metastatic to bones and bone marrow. The same treatment but with the epidoxorubicin dose of 180 mg/m2 induced a complete response in a patient with olfactory neuroblastoma. Administration of high dose Doxorubicin (75 mg/m2) seems feasible in association with irradiation treatment in patients with extraosseal Ewing sarcoma/PNET but the place of high dose chemotherapy within this setting remains to be determined.
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PMID:High-dose anthracyclines in the treatment of advanced primitive neuroectodermal tumors in adults--a single institution experience. 1120 63

Neuroblastoma is the most common extracranial solid tumor of childhood. N-type neuroblastoma cells (represented by SH-SY5Y and IMR32 cell lines) are characterized by a neuronal phenotype. N-type cell lines are generally N-myc amplified, express the anti-apoptotic protein Bcl-2, and do not express caspase-8. The present study was designed to determine the mechanism by which N-type cells die in response to specific cytotoxic agents (such as cisplatin and doxorubicin) commonly used to treat this disease. We found that N-type cells were equally sensitive to cisplatin and doxorubicin. Yet death induced by cisplatin was inhibited by the nonselective caspase inhibitor z-Val-Ala-Asp-fluoromethylketone or the specific caspase-9 inhibitor N-acetyl-Leu-Glu-His-Asp-aldehyde, whereas in contrast, caspase inhibition did not prevent doxorubicin-induced death. Neither the reactive oxygen species nor the mitochondrial permeability transition appears to play an important role in this process. Doxorubicin induced NF-kappa B transcriptional activation in association with I-kappa B alpha degradation prior to loss of cell viability. Surprisingly, the antioxidant and NF-kappa B inhibitor pyrrolidine dithiocarbamate blocked doxorubicin-induced NF-kappa B transcriptional activation and provided profound protection against doxorubicin killing. Moreover, SH-SY5Y cells expressing a super-repressor form of I-kappa B were completely resistant to doxorubicin killing. Together these findings show that NF-kappa B activation mediates doxorubicin-induced cell death without evidence of caspase function and suggest that cisplatin and doxorubicin engage different death pathways to kill neuroblastoma cells.
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PMID:NF-kappa B activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells. 1167 90

The signaling pathway for DNA damaging drug-triggered apoptosis was examined in a chemosensitive human neuroblastoma cell line, SH-SY5Y. Doxorubicin and etoposide induce rapid and extensive apoptosis in SH-SY5Y cells. After the drug treatment, p53 protein levels increase in the nucleus, leading to the induction of its transcription targets p21(Waf1/Cip1) and MDM2. Inactivation of p53, either by the human papillomavirus type 16 E6 protein or by a dominant-negative mutant p53 (R175H), completely protects SH-SY5Y cells from drug-triggered apoptosis. Cytochrome c and caspase-9 function downstream of p53 in mediating the drug-triggered apoptosis in SH-SY5Y cells. In drug-treated cells, cytochrome c is released, and caspase-9 becomes activated. Inactivation of p53 blocks cytochrome c release and caspase-9 activation. Furthermore, drug-induced cell death can be prevented by expression of a dominant-negative mutant of caspase-9. These findings define a molecular pathway for mediating DNA damaging drug-induced apoptosis in the human neuroblastoma SH-SY5Y cells and suggest that inactivation of essential components of this apoptotic pathway may confer drug resistance on neuroblastoma cells.
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PMID:p53 mediates DNA damaging drug-induced apoptosis through a caspase-9-dependent pathway in SH-SY5Y neuroblastoma cells. 1247 64

Three parental neuroblastoma cell lines and nine derived lines resistant to Vincristin, Doxorubicin and Cisplatin, respectively, using CGH were studied. CGH profiles of all three parental cell lines were obtained using DNA from a healthy volunteer as reference DNA. Labeled DNA from each of the drug resistant daughter cell lines and labeled DNA from their parental sensitive cell lines were hybridized to obtain a comparison of gains and losses that accompanied the development of resistance for that particular drug. All three parental cell lines were characterized by typical findings for high risk neuroblastoma: N-myc amplification, gain of 17q, and loss of 1p36.2-36.3. Acquired drug resistance in the neuroblastoma cell lines appeared to be accompanied by a large array of DNA sequence copy number changes. The regions frequently affected in chemo-resistant cell lines included gains of 13q14.1-32, and 7q11.2-31.3, 4 q. Amplifications were seen at 7q 21.1 consistent with MDR1 amplification in UKF-NB-2 VCR, UKF-NB-3 DOXO, UKF-NB-4 VCR, and UKF-NB-4 DOXO, but not in any Cisplatin resistant line. All Cisplatin and Doxorubicin and two Vincristin resistant line (UKF-NB-2 VCR and UKF-NB-4 VCR) had a deletion of part of 19q or the whole 19 chromosome. All lines resistant to Vincristin or Doxorubicin and two Cisplatin resistant lines (UKF-NB-2 CDDP and UKF-NB-4 CDDP) had a deletion of at least part of 17q, UKF-NB-4 DOXO had deletion of the whole chromosome 17. The loss of 17q may cause chemoresistance by deletion of topoisomerase IIalpha gene. Deletion of 19 q in all but one chemo-resistant lines may influence of cytochromes P450 genes which are located on 19q13.2. Also gains of 15q 22, which were detected in UKF-NB-4 VCR, UKF-NB-2 DOXO and UKF-NB-4 DO X O, may affect other cytochromes P450 genes.
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PMID:Characterization of drug-resistant neuroblastoma cell lines by comparative genomic hybridization. 1615 87

Human serum albumin (HSA) nanoparticles represent promising drug carrier systems. Binding of cytostatics to HSA nanoparticles may diminish their toxicity, optimise their body distribution and/or may overcome multidrug resistance. In the present study, doxorubicin-loaded HSA nanoparticle preparations were prepared. Doxorubicin was loaded to the HSA nanoparticles either by adsorption to the nanoparticles' surfaces or by incorporation into the particle matrix. Both loading strategies resulted in HSA nanoparticles of a size range between 150nm and 500nm with a loading efficiency of 70-95%. The influence on cell viability of the resulting nanoparticles was investigated in two different neuroblastoma cell lines. The anti-cancer effects of the drug-loaded nanoparticles were increased in comparison to doxorubicin solution. Based on these result a standard protocol for the preparation of doxorubicin-loaded HSA nanoparticles for further antitumoural studies was established.
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PMID:Preparation, characterisation and maintenance of drug efficacy of doxorubicin-loaded human serum albumin (HSA) nanoparticles. 1747 65

Neuroblastoma (NB) and Ewing's sarcoma (ES) represent the most common extracranial solid tumors of childhood. Heat shock proteins (HSP) are elevated in cancer cells and their over-expression was correlated to drug-resistance. In this work we identified the HSP by a sensitive proteomic analysis of NB and ES cell lines, then, we studied the HSP response to doxorubicin. Some identified HSP were constitutively more expressed in NB than in ES cells. Doxorubicin-stimulated HSP response only in NB cells. Quercetin was found to inhibit HSP expression depleting heat shock factor 1 (HSF1) cellular stores. Quercetin caused a higher anti-proliferative effect in NB (IC(50): 6.9 +/- 5.8 mumol/L) than in ES cells (IC(50): 85.5 +/- 53.1 mumol/L). Moreover, quercetin caused a very pronounced doxorubicin sensitizing effect in NB cells (241 fold IC(50) decrease) and a moderate effect in ES cells. HSP involvement in NB cells sensitization was confirmed by the silencing of HSF1. Quercetin treatment and HSF1 silencing increased the pro-apoptotic effect of doxorubicin. In conclusion, the higher HSP levels, observed in NB cells, did not confer increased resistance to doxorubicin; on the contrary, HSP inhibition by quercetin or gene silencing caused higher sensitization to doxorubicin. These results may have a potential application in the treatment of NB.
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PMID:Inhibition of heat shock proteins (HSP) expression by quercetin and differential doxorubicin sensitization in neuroblastoma and Ewing's sarcoma cell lines. 1768 Sep 92

The transcription factor nuclear factor-kappaB (NF-kappaB) plays a central role in stress-induced transcriptional activation and has been implicated in chemoresistance of cancers. In the present study, we investigated the role of NF-kappaB in inducible chemoresistance of neuroblastoma. Doxorubicin, VP16 and the cytotoxic ligand TRAIL trigger NF-kappaB activation, whereas cisplatin and taxol have no impact on NF-kappaB activity. Specific inhibition of NF-kappaB activation by overexpression of dominant-negative mutant IkappaBalpha-super-repressor does not alter cell death upon doxorubicin or VP16 treatment, although it prevents doxorubicin- or VP16-mediated NF-kappaB activation. By comparison, inhibition of TRAIL-stimulated NF-kappaB activation by IkappaBalpha-superrepressor or the small molecule NF-kappaB inhibitor BMS-345541 significantly enhances TRAIL-induced apoptosis, pointing to an antiapoptotic function of NF-kappaB in TRAIL-mediated apoptosis. Analysis of signaling pathways reveals that NF-kappaB inhibition prevents TRAIL-triggered up-regulation of Mcl-1, promoting TRAIL-induced cytochrome c release and activation of caspases. Accordingly, knockdown of Mcl-1 by RNA interference significantly enhances TRAIL-induced apoptosis and also increases sensitivity of neuroblastoma cells to CD95- or chemotherapy-induced apoptosis. In conclusion, NF-kappaB regulates apoptosis in a stimulus-specific manner in neuroblastoma cells and confers protection against TRAIL-induced apoptosis. By demonstrating that NF-kappaB inhibition sensitizes neuroblastoma cells for TRAIL-induced apoptosis, our findings have important implications. Thus, NF-kappaB inhibitors may open new perspectives to potentiate the efficacy of TRAIL-based protocols in the treatment of neuroblastoma.
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PMID:Sensitization of neuroblastoma cells for TRAIL-induced apoptosis by NF-kappaB inhibition. 1906 52

A variety of mechanisms maintain the integrity of the genome in the face of cell stress. Cancer cell response to chemotherapeutic and radiation-induced DNA damage is mediated by multiple defense mechanisms including polo-like kinase 1 (Plk-1), protein kinase B (Akt-1), and/or p53 pathways leading to either apoptosis or cell cycle arrest. Subsequently, a subpopulation of arrested viable cancer cells may remain and recur despite aggressive and repetitive therapy. Here, we show that modulation (activation of Akt-1 and Plk-1 and repression of p53) of these pathways simultaneously results in paradoxical enhancement of the effectiveness of cytotoxic chemotherapy. We demonstrate that a small molecule inhibitor, LB-1.2, of protein phosphatase 2A (PP2A) activates Plk-1 and Akt-1 and decreases p53 abundance in tumor cells. Combined with temozolomide (TMZ; a DNA-methylating chemotherapeutic drug), LB-1.2 causes complete regression of glioblastoma multiforme (GBM) xenografts without recurrence in 50% of animals (up to 28 weeks) and complete inhibition of growth of neuroblastoma (NB) xenografts. Treatment with either drug alone results in only short-term inhibition/regression with all xenografts resuming rapid growth. Combined with another widely used anticancer drug, Doxorubicin (DOX, a DNA intercalating agent), LB-1.2 also causes marked GBM xenograft regression, whereas DOX alone only slows growth. Inhibition of PP2A by LB-1.2 blocks cell-cycle arrest and increases progression of cell cycle in the presence of TMZ or DOX. Pharmacologic inhibition of PP2A may be a general method for enhancing the effectiveness of cancer treatments that damage DNA or disrupt components of cell replication.
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PMID:Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms. 1956 15


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