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

The positron-emitting glucose analogue 18F-2-fluoro-2-deoxy-d-glucose (FDG) was evaluated for its accretion into the following subcutaneous human tumor xenografts in nude mice: B-cell lymphoma (Namalwa or Raji), ovarian carcinoma (HTB77), colon cancer (SW948), choriocarcinoma (BEWO), bladder cancer (UM-UC-2), renal cell carcinoma (UM-RC-3), neuroblastoma (Mey), melanoma (HTB63), and small cell lung carcinoma (NCI69). Two hours postinjection, tumor uptakes ranged from 0.027 (colon cancer) to 0.125% kg injected dose/g (melanoma); and was greater than 0.085 in the Namalwa lymphomas and the renal cell carcinomas. Tumor-blood ratios of up to 23:1 were seen 2 hours postinjection (melanoma) with a mean tumor-blood ratio for all tumors of 12.3 +/- 1.8. Uptake in the other tumors was intermediate. When evaluated, tumor uptake was slightly greater at 1 than at 2 hours postinjection, although target-background ratios were generally higher at 2 hours postinjection. This compound, FDG, may have broad applicability as a tracer for positron-emission tomographic imaging of many human malignancies.
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PMID:18F-2-deoxy-2-fluoro-D-glucose uptake into human tumor xenografts. Feasibility studies for cancer imaging with positron-emission tomography. 200 43

Ifosfamide/mesna was given to 97 patients who had malignant solid tumors diagnosed before they were 21 years of age. Patients received 1.6 g/m2 ifosfamide daily x 5, given i.v. over 15 min, followed by 400 mg/m2 i.v. mesna at 15 min and 4 and 6 h after ifosfamide. Responses were noted in patients with osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma and other soft-tissue sarcomas, rhabdoid tumor, neuroblastoma, Wilms' tumor, primitive neuroectodermal tumor, retinoblastoma, germ-cell tumors, and B-cell lymphoma. Toxicity included mild to moderate nausea and vomiting, transient, reversible myelosuppression, transient elevations of serum blood urea nitrogen (BUN) and creatinine and liver enzymes, infections, and self-limiting neurotoxicity characterized by changes in mental status, motor dysfunction, cranial nerve palsy, cerebellar dysfunction, and seizures. Neurotoxic symptoms were generally seen in patients who had previously received cisplatin. Ifosfamide is an important alkylating agent that should be combined with other agents in phase II and III trials. Alternate dose schedules should also be investigated.
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PMID:Ifosfamide in pediatric malignant solid tumors. 250 57

Ifosfamide was given to 61 patients with malignant solid tumors diagnosed before the age of 21 years. In this phase II study, all patients received 1.6 g/m2/day X 5 iv over 15 minutes followed by mesna at a dose of 400 mg/m2 iv at 15 minutes and 4 and 6 hours after ifosfamide. Responses were observed in five of 15 patients with osteosarcoma, two of ten with neuroblastoma, two of six with Wilms' tumor, two of five with rhabdomyosarcoma, four of eight with other soft tissue sarcomas, one of one with retinoblastoma, one of two with germ cell tumors, one of one with B-cell lymphoma, and one of one with a primitive neuroectodermal tumor. Fifty-nine of 61 patients had received prior alkylating agent therapy which included cyclophosphamide, cisplatin, mechlorethamine, melphalan, or dacarbazine. Fourteen of 19 responses developed in patients whose tumors were resistant to treatment with cyclophosphamide. A patient with malignant Schwannoma who had received no prior chemotherapy developed a complete response which lasted 12 months. A patient with brain metastases of osteosarcoma has had complete response for greater than 2 years. Complete response was also observed in a patient with B-cell lymphoma. Toxicity consisted of mild to moderate nausea and vomiting, transient reversible myelosuppression, occasional elevation of serum BUN or creatinine, and transient neurotoxicity characterized by somnolence, confusion, weakness, tremor, hallucinations, or seizures. We conclude that ifosfamide is an important alkylating agent without apparent complete cross-resistance with cyclophosphamide, and as such should be further investigated for determination of its activity in patients with pediatric neoplasms and considered for incorporation into phase II-III trials for certain tumors.
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PMID:Phase II trial of ifosfamide in children with malignant solid tumors. 310 34

Expression of the RCK gene, which is a target gene on 11q23 of the t(11;14) (q23;q32) translocation in the B-cell lymphoma cell line RC-K8, was studied by Northern and Western blot analyses. The RCK gene product is a member of the D-E-A-D box protein/RNA helicase family. With the use of Northern blot analysis, a 7.5-kb transcript of the RCK gene was shown to be expressed ubiquitously in human and mouse tissues. Polyclonal antibodies against the RCK gene product were raised, and the RCK gene expression pattern was examined in human and mouse tissues. Two different polyclonal anti-rck antibodies detected a specific 54-kilodalton product named rck/p54 in the majority of human and mouse tissues tested by Western blot analysis. However, rck/p54 was shown to be very low in the human brain and was not detectable in lumbar muscle and lung tissues, although RCK mRNA is abundantly present in these tissues. It is of interest that malignant transformed human cells arising from tissues with low or no expression of rck/p54, such as neuroblastoma, glioblastoma, rhabdomyosarcoma, and lung cancer cell lines, produced a moderate amount of rck/p54 protein, suggesting that rck/p54 plays a role in tumorigenesis. In addition, the rck/p54 protein was localized to cytoplasm by immunostaining with the use of laser microscopy and by subcellular fractionation.
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PMID:The rck/p54 candidate proto-oncogene product is a 54-kilodalton D-E-A-D box protein differentially expressed in human and mouse tissues. 761 84

There is a large increase in lymphoid malignancy in A-T patients and a total absence of myeloid tumors. Penetrance of the tumor phenotype is about 10% to 15% by early adulthood. The increase in lymphoid malignancy includes both B- and T-cell tumors. However, young A-T patients do not show an increased susceptibility to cALL, and the UK data suggest that B-cell lymphoma occurs in older A-T children. T-cell tumors may occur at any age and may be T-ALL, T-cell lymphoma, or T-PLL; most strikingly, there may be a fourfold to fivefold increased frequency of T-cell tumors compared with that of B-cell tumors in these patients. If this is correct, it is possible that a significant proportion of all T-ALL/T-cell lymphoma in infants might be associated with undiagnosed A-T. The age range and sex predominance for T-ALL may be different for A-T and non-A-T patients and the age range for T-PLL may also be different in A-T and non-A-T patients. There is clearly some uncertainty concerning the ratio of T-cell to B-cell tumors in A-T, but this could be clarified by the publication of all tumors that occur in the disorder. In contrast, 8 of 9 tumors reported in NBS, which shows the same cellular features as A-T, were lymphomas and none was a leukemia. There are several indicators of genetic heterogeneity in A-T that suggest that not all patients are equally susceptible to all T-cell tumor types. Concordance for tumor type within individual families suggests that particular gene defects may be associated with particular tumor types. The logical extrapolation of this argument is that some patients may not have any increased risk for B-cell tumors at all or even to all T-cell types but only to a particular type of T-cell tumor. What is the cause of the increased predisposition to leukemia/lymphoma in A-T patients? There is no evidence that the immunodeficiency in A-T is related to this predisposition. One of the major findings in all A-T patients is the increase in V(D)J-mediated chromosome rearrangement observed in T lymphocytes. Particular chromosome translocations in T cells, involving a break in a TCR gene, are characteristically associated with either T-ALL or T-PLL in non-A-T patients. The majority of T-cell tumors in A-T are T-ALL and T-cell lymphoma, about which virtually nothing is known chromosomally, and the assumption is that the increased number of translocations leads to the increased level of these tumors. In older T patients, the expansion of specific translocation T-cell clones has been followed to the point to which they develop into T-PLL. All the evidence, therefore, suggests that the A-T mutation in the homozygous state allows a large increase in production of translocations formed at the time of V(D)J recombination, and this leads to the increased predisposition to leukemia. The general increased predisposition to T-cell tumors compared with B-cell tumors in A-T patients may be related to a preferential occurrence of translocations in T cells. Relatively little is known about translocations in circulating B lymphocytes in normal individuals, but A-T siblings have been shown to have clonal chromosome rearrangements of both B and T cells, simultaneously, although in these siblings the T-cell clones occupied all the T-cell compartment and the B-cell clones were small. An important inference from these facts is that the A-T defect preferentially affects immune system gene recombination in T cells rather than B cells. Recent evidence suggests that the V(D)J recombination machinery is not identical or is not regulated identically in T- and B-cell progenitors. This finding is consistent with the hypothesis that V(D)J rejoining in the majority, at least, of A-T patients may be preferentially deficient in T cells compared with B cells giving rise to the greatly increased number of translocations and T-cell tumors. Carbonari et al proposed that the recombination defect in A-T cells affected both Ig isotype switching and TCR rearrangeme
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PMID:Leukemia and lymphoma in ataxia telangiectasia. 855 63

Blood group-related antigens have been attractive targets for immunotherapy of cancer since their initial identification as cancer-related antigens. However, available information on the relative expression of most of these antigens on human malignant and normal tissues has been insufficient for selecting optimal antigens and tumors for immune attack. In this study, the distribution of the blood group-related antigens TF, Tn, sTn, Le(a), sialyl Le(a), Le(b), Le(x), sialyl Le(x), polyfucosyl Le(x) and Le(y) on 13 types of cancer and 16 normal tissues was compared. Our results show that sTn is strongly expressed on cancers of breast, colon, stomach, ovary, prostate and uterus; Tn on prostate cancer; TF on cancers of breast, colon, ovary, prostate and uterus; Le(y) on the cancers of colon, lung, pancreas and ovary; Le(a) and Le(x) on gastric cancer; and sialyl Le(a) and sialyl Le(x) on colon cancer. The complete absence of these antigens on cancers of neuroectodermal or mesodermal origin including melanoma, sarcoma, neuroblastoma and B cell lymphoma is as striking as their widespread presence on tumors of epithelial origin. Normal tissues were also tested. Tn and Le(b) were only detected on gastric and ovarian epithelia; sTn on Leydig cells of testis in addition to gastric and ovarian epithelia; Le(x) and sialyl Le(x) on polymorphonuclear leukocytes; and TF, Le(a), sialyl Le(a), Le(x), sialyl Le(x), polyfucosyl Le(x) and Le(y) on epithelia from a variety of tissues.
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PMID:Selection of tumor antigens as targets for immune attack using immunohistochemistry: II. Blood group-related antigens. 933 9

Therapeutic use of radionuclides includes 131I for thyroid cancer and hyperthyroid Graves' disease, 89SrCl3 for metastatic bone tumors, 131I-MIBG for malignant pheochromocytoma and neuroblastoma, and radioimmunotherapies. 131I is concentrated in 60-70% of metastases from differentiated thyroid cancer following total thyroidectomy. Radioiodine uptake in metastatic lesions is greater in younger patients than in older ones. Hypothyroidism is often mild or even absent in patients with a large amount of tumor tissue, indicating that thyroid hormones produced by highly differentiated tumors compensate partially or even completely for hypothyroidism following total thyroidectomy. Adequate uptake of 131I has been reported to be associated with significant reduction in the size and number of metastases, and with lower recurrence and higher survival rates. Other favorable factors for longer survival are younger age, well-differentiated histological type, small disease extent, and early discovery of metastases. Older patients with extensive metastases and/or bulky tumor masses in the bone have a poor prognosis. Therefore, it is important to discover metastases as early as possible, when patients are still young. Long-term follow-up with periodic thyroglobulin measurements and imaging studies is strongly recommended. In Japan, 131I treatment for Graves' disease is performed only in selected patients in whom antithyroid drugs cannot be used because of side effects or not effective, considering the high prevalence of permanent hypothyroidism. 89SrCl3 is useful for reducing pain due to bone metastases of malignant tumors. 131I-MIBG therapy is effective for improvement of QOL in some patients with metastatic malignant pheochromocytoma. Radioimmuno-therapy using anti-CD20 has been used successfully in clinical application in patients with malignant B cell lymphoma.
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PMID:[Recent progress in radionuclide therapy]. 1114 Mar 21

In this study cytological findings in specimens of cerebrospinal fluid (CSF) of central nervous system (CNS) tumours (16 primaries, 57 metastatic and 12 suspicious) are presented, which were diagnosed over a period of 7 years in 85 patients (50 females and 35 males) with an age range of 2-76 years. The follow-up included information from clinicians and a review of medical charts, histological correlation and/or further investigations following cytodiagnosis. The patients clinically presented with signs and symptoms of meningeal involvement. The primary tumours included six medulloblastomas, eight gliomas (four glioblastomata multiforme, two anaplastic astrocytomas, and two ependymomas) and two germinomas. The metastatic tumours were 14 melanomas, 19 breast carcinomas, four leukaemias, six B-cell lymphomas, five adenocarcinomas of gastrointestinal origin, seven carcinomas of lung, one retinoblastoma and one neuroblastoma. Twelve cases were reported as suspicious. On further investigations, four of these were from a primary tumour (two glioblastomata multiforme and two anaplastic astrocytomas) while the other eight cases were of a metastasis (one B-cell lymphoma, three breast carcinomas, three melanomas and one adenocarcinoma of gastrointestinal origin). Using a panel of selective immunostains in some of the cases supported the cytological diagnosis and this was considered useful in furthering cytodiagnosis. In 75 of the patients the CSF samples were obtained on a spinal tap while in 10 patients the samples were received as ventricular CSF. There were no false-positive cases. The results of our study suggest that CSF cytology in the diagnosis of CNS tumours is quite reliable and reflects involvement of leptomeninges or the ventricles. Furthermore, the use of selective immunostains can be helpful in confirming the cytological impression and source of the tumour.
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PMID:Cytodiagnosis of neoplasms of the central nervous system in cerebrospinal fluid samples with an application of selective immunostains in differentiation. 1474 90

This laboratory and others have shown that agents that inhibit the in vitro catalytic activity of methionine aminopeptidase-2 (MetAP2) are effective in blocking angiogenesis and tumor growth in preclinical models. However, these prototype MetAP2 inhibitors are clearly not optimized for therapeutic use in the clinic. We have discovered an orally active class of MetAP2 inhibitors, the anthranilic acid sulfonamides exemplified by A-800141, which is highly specific for MetAP2. This orally bioavailable inhibitor exhibits an antiangiogenesis effect and a broad anticancer activity in a variety of tumor xenografts including B cell lymphoma, neuroblastoma, and prostate and colon carcinomas, either as a single agent or in combination with cytotoxic agents. We also have developed a biomarker assay to evaluate in vivo MetAP2 inhibition in circulating mononuclear cells and in tumors. This biomarker assay is based on the N-terminal methionine status of the MetAP2-specific substrate GAPDH in these cells. In cell cultures in vitro, the sulfonamide MetAP2 inhibitor A-800141 caused the formation of GAPDH variants with an unprocessed N-terminal methionine. A-800141 blocked tumor growth and MetAP2 activity in a similar dose-response in mouse models, demonstrating the antitumor effects seen for A-800141 are causally connected to MetAP2 inhibition in vivo. The sulfonamide MetAP2 inhibitor and GAPDH biomarker in circulating leukocytes may be used for the development of a cancer treatment.
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PMID:Correlation of tumor growth suppression and methionine aminopetidase-2 activity blockade using an orally active inhibitor. 1825 27

Recent studies have suggested that first and second generation antipsychotics (FGAs and SGAs) have different neuroprotective effects. However, the molecular mechanisms of SGAs are not fully understood, and investigations into changes in intracellular signaling related to their neuroprotective effects remain scarce. In the present study, we compared the SGA aripiprazole with the FGA haloperidol in SH-SY5Y human neuroblastoma cells via brain-derived neurotrophic factor (BDNF)-mediated signaling, notably BDNF, glycogen synthase kinase-3beta (GSK-3beta), and B cell lymphoma protein-2 (Bcl-2). We examined the effects of aripiprazole (five and 10 microM) and haloperidol (one and 10 microM) on BDNF gene promoter activity in SH-SY5Y cells transfected with a rat BDNF promoter fragment (-108 to +340) linked to the luciferase reporter gene. The changes in BDNF, p-GSK-3beta, and Bcl-2 levels were measured by Western blot analysis. The haloperidol was not associated with a significant difference in BDNF promoter activity. In contrast, aripiprazole was associated with increased BDNF promoter activity only with a dose of 10 microM (93%, p<0.01). Treatment with aripiprazole at 10 microM increased the levels of BDNF by 85%, compared with control levels (p<0.01), whereas haloperidol had no effect. Moreover, cells treated with aripirazole effectively increased the levels of GSK-3beta phosphorylation and Bcl-2 at doses of five and 10 microM (30% and 58% and 31% and 80%, respectively, p<0.05 or p<0.01). However, haloperidol had no effects on p-GSK-3 beta and Bcl-2 expression. This study showed that aripiprazole, but not haloperidol, appeared to offer neuroprotective effects on human neuronal cells. The actions of signaling systems associated with BDNF may represent key targets for both aripiprazole and haloperidol, but the latter may be associated with distinct effects. These differences might be related to the different therapeutic effects of FGAs and SGAs in patients with schizophrenia.
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PMID:Differential effects of aripiprazole and haloperidol on BDNF-mediated signal changes in SH-SY5Y cells. 1919 96


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