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)

SV40 large T-antigen (LTa) gene-induced immortalized rat dopamine-producing nerve cells (IRB3AN27), which produce LTa protein and divide in vitro, do not divide and do not produce LTa protein when transplanted into striatum of adult rats. This suggests the presence of LTa gene-inhibiting factors in brain. Here we report that rat brain soluble fraction (SF) contains factors which specifically inhibit LTa gene activity in vitro. The brain SF inhibited LTa protein levels and the growth of IRB3AN27 cells and 2RSG cells (LTa gene-induced immortalized rat parotid acinar cells) in vitro, but it stimulated the growth of spontaneously immortalized human parotid acinar cells (2HPC8) and had no effect on the proliferation of murine neuroblastoma cells (NBP2) and rat glioma cells (C-6) in culture. In contrast, the liver SF inhibited the growth of all cell lines tested at varying degrees and thus lacked specificity with respect to LTa gene activity. The presence of specific LTa gene-inhibiting factors in the brain and general tumor growth-inhibiting factors in the liver may provide some of the mechanisms of protection against in vivo carcinogenesis.
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PMID:Brain contains inhibiting factors specific to the large T-antigen gene. 946 88

Merkel cell carcinoma (MCC) is a malignant tumor of the skin with a well-established neuroendocrine phenotype but an unknown histogenetic origin. Cytogenetic and molecular studies have shown evidence for genetic changes on the distal portion of chromosome 1p in different tumors with well-established neuroendocrine origins, specifically neuroblastomas, malignant melanomas, and pheochromocytomas. Involvement of chromosome 1 in MCC recently has been demonstrated by cytogenetic analysis and analysis of loss of heterozygosity (LOH) in metastatic tumor tissue. We performed analysis of LOH of the distal portion of chromosome 1p in paraffin material of 10 primary MCCs after tissue microdissection, using the polymorphic markers D1S160, D1S243, D1S468, D1S1646, and D1S1598. Seven of 10 analyzed MCCs shared a distal deletion involving 1p35-36. None of the cases showed 1p involvement proximal to 1p35. The findings are similar to those described for malignant melanoma, pheochromocytoma, and neuroblastoma, tumors known to originate from neural crest cells. In conjunction with previous cytogenetic data, we conclude that Merkel cell carcinogenesis shares pathogenetic mechanisms with other neoplasms of neural crest derivation.
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PMID:Genetic changes associated with primary Merkel cell carcinoma. 957 74

Mononitrosocaffeidine (MNC) and dinitrosocaffeidine (DNC) are new N-nitroso compounds obtained from in vitro nitrosation of caffeidine, a hydrolysis product of caffeine present in a typically made and widely consumed tea from Kashmir (India), a high incidence area of esophageal and stomach cancer. The chemical synthesis, in vitro metabolic studies and mutagenicity of the compounds has been previously reported. DNC, a nitrosamide is highly mutagenic both with and without metabolic activation whereas MNC, like several other aromatic asymmetric nitrosamines, does not exhibit genotoxic or mutagenic properties. We now report the results of the first carcinogenicity experiments on chronic oral administration of these compounds in BD-IX rats. The acute LD50 of MNC and DNC were about 1300 and 230 mg/kg b.w., respectively. Lung oedema and gastrointestinal haemorrhages were the first symptoms of intoxication observed after 2 days for both the compounds. All three dose groups of MNC treated rats showed localization of tumours in nasal cavity (93.9-100% of all malignant tumours). The tumours were histologically diagnosed as neuroepitheliomas of the olfactory epithelium (neuroblastoma of the bulbus olfactorii) and squamous cell carcinoma of the nasal cavity in the ratio of 3:1. No tumours of the nasal cavity were observed in the untreated controls. DNC, in contrast, induced squamous cell carcinoma of forestomach in 100% animals at low and high doses, of which nearly half the tumours metastasized predominantly into the peritoneum. No forestomach tumours were seen in the untreated controls. The data presented here clearly show the potential for induction of malignant tumours and distinct organ-specificity by MNC and DNC in rats, and support the postulate that a chronic exposure to these compounds may provide a carcinogenic risk for high incidence of gastrointestinal cancers in Kashmir.
Carcinogenesis 1998 May
PMID:Caffeine-derived N-nitroso compounds. V. Carcinogenicity of mononitrosocaffeidine and dinitrosocaffeidine in bd-ix rats. 963 85

Genistein is a specific inhibitor of protein tyrosine kinase (PTK) and is considered as a therapeutic candidate for various cancers. In this paper we investigate the effects of genistein on cell proliferation and differentiation in neuroblastoma (NB) cell lines and its possible mechanism of action. Genistein substantially inhibited the growth of five (N2A, JC, SKNSH, MSN and Lan5) of the six tumor cell lines examined in a dose-dependent manner with an IC50 value of approximately 5 microg/ml. The exception was GC cells. N2A cells were treated with genistein for 6 days and exhibited morphological features of differentiation, as evidenced by the development of dendritic extensions. Terminal deoxynucleotidyl transferase (TDT) histochemical staining showed a significant elevation in darkly stained nuclei in genistein-treated N2A cells compared with controls, indicating the occurrence of apoptosis. Fluorescent quantitation of DNA fragments confirmed apoptosis in genistein-treated N2A cells. To further elucidate the possible mechanisms by which genistein modulates NB cell growth and differentiation we investigated the effect of genistein on the activities of PTK and mitogen-activated protein (MAP) kinase and N-myc proto-oncogene expression in N2A cells. The results showed that genistein down-regulated intrinsic PTK activity by approximately 33% and inhibited insulin-like growth factor (IGF)-stimulated PTK activity by 75%. The effect of genistein on the intrinsic activity of MAP kinase was insignificant. In addition, genistein significantly reduced N-myc expression in a dose-dependent fashion. Our study suggests that genistein arrests cell growth and induces NB cell differentiation by mediating apoptosis and modulating PTK activity and N-myc proto-oncogene expression.
Carcinogenesis 1998 Jun
PMID:Genistein modulates neuroblastoma cell proliferation and differentiation through induction of apoptosis and regulation of tyrosine kinase activity and N-myc expression. 966 36

Fragile sites are chromosome bands that do not manifest a presumed breakage pattern. Identification of fragile sites is a way to investigate the mechanism of carcinogenesis because the fragility at a specific chromosome position may be the causation of an associated cancer. A problem in the identification of fragile sites is the high false positive rate arising from simultaneously carrying out a large number of significance tests. To control it, we propose to find a reference study to confirm the identification result of an objective study. We utilize the Bayesian concept for linking two studies. Basically, our method demonstrates a conservative way to take account of the prior information of a binomial parameter. The derived estimate of breakage probability can be interpreted as a resampling weighted sample-pooling method. It is applied to confirm the identification of fragile sites for a data set of neuroblastoma patients.
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PMID:A confirmation analysis method for identification of chromosomal fragile sites. 968 21

p73 gene, a new p53 homologue, has been identified: it supposedly acts as tumour suppressor gene in neuroblastoma. To clarify whether p73 might be involved in lung carcinogenesis, we examined p73 expression in resected lung cancer and paired normal lung in 60 cases using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). We also examined p73 gene status in three representative cases using Southern blot, and p53 gene alteration in 49 cases using PCR-single-strand conformation polymorphism (PCR-SSCP) and direct sequence. In 87% of the cases (52/60) p73 expression in tumour was more than twice as high as that in paired normal lung tissues, and the difference between p73 expression in tumour and normal lung tissue was significant (P < 0.0001). However, Southern blot analysis revealed that none of the cases showed p73 gene amplification. Compared with clinicopathological characteristics, p73 expression correlates significantly with histological differences and age of patient, independently (P < 0.05). Concerning p53 gene status, 43% (21/49) showed p53 gene alteration, but there was no correlation between p73 overexpression and p53 gene alteration. Our results suggest that need for further functional analysis of the role of p73 in lung carcinogenesis.
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PMID:The expression of p73 is increased in lung cancer, independent of p53 gene alteration. 1040 9

Accumulating evidence has demonstrated that aberration of the p53 tumour-suppressor gene is one of the pivotal genetic events in hepatocellular carcinogenesis. Recent reports suggest that the product of hepatitis B virus (HBV) interacts with p53 and that the hepatitis C virus (HCV) core protein reduces p53 expression. A novel p73 gene, which is related to p53, has recently been identified and mapped to chromosome 1p36.3, which is a locus of multiple tumour-suppressor genes for many cancers, including hepatocellular carcinoma (HCC) and neuroblastoma. Here, we investigated mRNA expression, allelotype and mutation of p73 in 48 HCCs obtained from untreated patients. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that p73 mRNA was expressed ubiquitously at low levels in all the tumour tissues, as well as in the adjacent normal liver tissues. The frequency of p73 loss of heterozygosity was observed in 20% of HCCs, but PCR-single strand conformation polymorphism (SSCP) analysis showed no mutations in the 48 tumours except for three types of polymorphisms. These results suggest that p73 may play a role in hepatocellular carcinogenesis in a different manner from a Knudson two-hit model. The regulatory mechanism of interaction between p73 and hepatitis viruses remains to be determined.
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PMID:Absence of mutation of the p73 gene localized at chromosome 1p36.3 in hepatocellular carcinoma. 1040 9

Vitamin A, its physiologic metabolites, and synthetic derivatives (retinoids) have been shown to have protective effects against the development of certain types of cancer. In addition, pharmacologic amounts of retinoids have been used with some success in the treatment of a few human tumors. The chemoprevention effect of retinoids is most likely exerted at the tumor-promotion phase of carcinogenesis. Retinoids block tumor promotion by inhibiting proliferation, inducing apoptosis, inducing differentiation, or a combination of these actions. Clinically, isotretinoin (13-cis-retinoic acid) significantly decreases the incidence of second primary tumors in patients with head-and-neck cancer and reduces appearance of non-melanoma skin cancer in patients with xeroderma pigmentosum. Retinoic acid has proved to be an effective treatment for promyelocytic leukemia. However, retinoid resistance limits its use as a single agent. Clinical trials are in progress to determine the efficacy of retinoids in treating other types of cancer such as neuroblastoma and breast carcinoma. The development of receptor-selective retinoids and selective inhibitors of retinoid metabolism may lead to further use of retinoids in both chemoprevention and treatment of cancer.
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PMID:Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. 1111 36

Inactivating germline mutations of the novel putative tumor-suppressor gene LKB1/STK11 at 19p13.3 have been shown to cause Peutz-Jeghers syndrome (PJS), an autosomal dominantly inherited disease characterized by a predisposition to mucocutaneous pigmentations, as well as various benign and malignant neoplasms. To elucidate the role of LKB1/STK11 in the carcinogenesis of primary and secondary human brain tumors, a total of 309 tumors were analyzed for loss of heterozygosity (LOH) at microsatellite loci D19S886, DI9S878, and D19S565. Low LOH rates were observed for glioma (17.3%, n = 139), meningioma (5.3%, n = 57), schwannoma (0%, n = 21), pituitary adenoma (18.8%, n = 16), primary CNS lymphoma, neuroblastoma, plasmocytoma, medulloblastoma, germinoma, and papilloma of the choroid plexus (6.6%, n = 15). In contrast, brain metastases exhibited a mean LOH frequency of 42.6% (n = 61), with breast (56.3%) and lung cancer metastases (58.3%) being most frequently affected. Genomic DNA sequencing of the complete coding region of LKB1/STK11 was performed in all brain metastases exhibiting LOH (n = 26); no mutation was revealed, but we did find a germline mutation in a PJS patient. Despite high LOH fiequencies at the 19p13.3 locus in carcinoma metastases to the brain and occasional mutations reported for certain primary carcinomas, there are no mutations in LKB1/STK11. This fact suggests that alterations of LKB1/STK11 occur relatively early in tumorigenesis and are rarely involved in the development of carcinoma metastases. Based on these findings, the genes adjacent to LKB1/STK11 may be relevant for the development of metastases to the brain from certain carcinomas.
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PMID:Frequent loss of heterozygosity at the 19p13.3 locus without LKB1/STK11 mutations in human carcinoma metastases to the brain. 1121 97

In spite of extensive research in molecular carcinogenesis, genes that can be considered primary targets in human carcinogenesis remain to be identified. Mutated oncogenes or cellular growth regulatory genes, when incorporated into normal human epithelial cells, failed to immortalize or transform these cells. Therefore, they may be secondary events in human carcinogenesis. Based on some experimental studies we have proposed that downregulation of a differentiation gene may be the primary event in human carcinogenesis. Such a gene could be referred to as a tumor-initiating gene. Downregulation of a differentiation gene can be accomplished by a mutation in the differentiation gene, by activation of differentiation suppressor genes, and by inactivation of tumor suppressor genes. Downregulation of a differentiation gene can lead to immortalization of normal cells. Mutations in cellular proto-oncogenes, growth regulatory genes, and tumor suppressor genes in immortalized cells can lead to transformation. Such genes could be called tumor-promoting genes. This hypothesis can be documented by experiments published on differentiation of neuroblastoma (NB) cells in culture. The fact that terminal differentiation can be induced in NB cells by adenosine 3',5'-cyclic monophosphate (cAMP) suggests that the differentiation gene in these cells is not mutated, and thus can be activated by an appropriate agent. The fact that cAMP-resistant cells exist in NB cell populations suggests that a differentiation gene is mutated in these cancer cells, or that differentiation regulatory genes have become unresponsive to cAMP. In addition to cAMP, several other differentiating agents have been identified. Our proposed hypothesis of carcinogenesis can also be applied to other human tumors such as melanoma, pheochromocytoma, medulloblastoma, glioma, sarcoma, and colon cancer.
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PMID:Differentiation genes: are they primary targets for human carcinogenesis? 1156 2


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