Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A transplantable rat pheochromocytoma in New England Deaconess Hospital (NEDH) was first described by WARREN in 1972. It is characterized by the documented association with systolic hypertension and the known presence of increased urinary metanephrines and vanilmadelic acid in tumor-bearing animals. The present report describes features of the transplantable tumor, our laboratories have noted, in five tumor transplantations starting in 1974. Tumor-bearing animals survive 49 +/- 5 days and die much sooner than aging, non-tumor-bearing litter mates. Gross measurements confirm the rapid growth of the primary tumor, although at autopsy, histologically proven metastatic foci are rarely seen. Polycythemia with or without increased erythropoietin (ESF) levels were not detected. Electronmicroscopic studies confirmed the presence in tumor tissue of the previously described intracytoplasmic granules. Further studies on this endocrine-associated transplantable tumor are warranted and feasible.
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PMID:Studies of a transplantable rat pheochromocytoma. 101 45

The efficacy of recombinant human erythropoietin (rHuEPO) on the increase in hemoglobin levels was assessed in patients with cisplatin (CDDP)-induced anemia older than 70 years. Furthermore, we compared the results obtained in this group of patients with those observed in other patients receiving rHuEPO for a CDDP-associated anemia with similar clinical features (chemotherapeutic regimen, primary tumor; CDDP cumulative dose) but of an age less than 70 years. Twenty patients older than 70 years with a CDDP-associated anemia (hemoglobin levels < 90 milligrams) received rHuEPO at the dose of 100 U/kg subcutaneously, three times a week. The control group consisted of 20 younger patients, anemic after CDDP chemotherapy, treated with rHuEPO. All patients were evaluable for response and toxicity. Hemoglobin concentrations showed a statistically significant increase after the 3rd, 6th and 9th week of therapy in both older (93.1 +/- 10.7, 103.5 +/- 8.2 and 102.7 +/- 8.2, respectively, vs. baseline, 84.6 +/- 4.9) and younger patients (95.3 +/- 11.7, 101.5 +/- 13.4 and 101.9 +/- 8.7, respectively, vs. baseline, 86.6 +/- 4.0). Furthermore, 30% of older patients required blood transfusions versus 35% of younger patients, with the mean unit of blood transfused per patient being 0.7 U in elderly and 0.65 U in younger patients. Treatment was well tolerated with no significant side effects. The CDDP-induced anemia seems to be corrected by rHuEPO also in elderly patients, without differences with respect to younger patients.
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PMID:Recombinant human erythropoietin treatment in elderly cancer patients with cisplatin-associated anemia. 763 61

The ELM erythroleukemia is novel in that long-term survival of leukemic cells in culture (ELM-D cells) is dependent on contact with a bone marrow-derived stromal feeder cell layer. However, a number of stroma-independent (ELM-I) mutants that vary in their ability to differentiate in vitro in response to erythropoietin and interleukin-3 have been derived. We have attempted to define the genetic changes responsible for these different phenotypes. At the p53 locus in the primary leukemic cells, one copy of the gene has been lost whereas the other contains an 18-bp depletion, implicating its mutation as an early step in the development of the leukemia. Changes in ets gene expression have also been found. The Fli-1 gene region is rearranged in the primary tumor because of the insertion of a retrovirus inserted upstream of one Fli-1 allele, but this does not result in Fli-1 gene activation in any of the ELM-D or ELM-I cell lines except one. It seems significant that this line is the only one to have lost the ability to differentiate in response to erythropoietin. In addition, up-regulation of erg is associated with stromal cell-independent growth, since all ELM-I mutants have moderate levels of erg mRNA, whereas only low or undetectable levels are found in primary leukemic cells in vivo or in ELM-D cells in vitro. This up-regulation of erg mRNA seems to be important for stromal cell-independent growth, since ELM-D cells show elevated expression of the erg gene after separation from stromal cells. This seems to be made permanent in ELM-I mutants, since they do not down-regulate erg mRNA when grown in contact with stromal cells. We therefore propose that ets family members regulate both the survival and differentiation of erythroid cells.
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PMID:Differentiation arrest and stromal cell-independent growth of murine erythroleukemia cells are associated with elevated expression of ets-related genes but not with mutation of p53. 835 1

Hepatoblastoma is the most common malignant pediatric liver tumor. The molecular mechanisms involved in the pathogenesis of hepatoblastoma are unknown. Cell lines can be valuable tools in the study of tumor biology, but only few hepatoblastoma cell lines have been established. We explanted tumor tissue from human hepatoblastomas to generate cell lines. A continuous cell line (HepT1) was established from a human hepatoblastoma with predominant embryonal differentiation. The HepT1 cell line was characterized by immunohistochemistry, electron microscopy, cytogenetics, and molecular genetic analysis. In addition, the cultured cells were xenografted into nude mice and the resulting tumors compared with the original tumor. The cells grew in epithelial clusters, and expressed cytokeratins and alpha-fetoprotein. Injection of HepT1 cells into nude mice gave rise to serially transplantable subcutaneous tumors. The cell line as well as the xenotransplants displayed the phenotypic and genotypic characteristics of the primary tumor. Ultrastructural analysis demonstrated desmosomal junctions and the formation of bile canaliculi. Cytogenetic analysis showed a near tetraploid karyotype with structural and numerical aberrations of chromosomes 1p, 6, 9, 11q, 13q, 15p, and 20 and both single and double minute chromosomes. In PCR-based microsatellite analysis of chromosome arm 11p, a loss of heterozygosity at all informative loci including the WT-1 and IGF2 genes was detected. Intratumoral erythropoiesis, a characteristic feature of hepatoblastomas, was present in the primary tumor as well as in HepT1 xenotransplants. We therefore studied the expression of erythropoietic cytokines in these cells and found both erythropoietin and stem cell factor. The HepT1 cell line displays characteristic cellular and molecular features of hepatoblastoma and we believe it will be a valuable tool for studies on the biology and pathogenesis of hepatoblastoma as well as on the differentiation of hepatocyte progenitor cells.
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PMID:Characterization of the continuous cell line HepT1 derived from a human hepatoblastoma. 860 90

Erythroleukemias induced by Friend Murine Leukemia Virus (F-MuLV) involve the insertional activation of the proto-oncogene Fli-1, and the inactivation of the p53 tumor suppressor gene. While the activation of Fli-1 is an early, primary transforming event, p53 mutations are correlated with the immortalization of erythroleukemic cells in culture. In this study we have further analysed the role of p53 loss in F-MuLV induced erythroleukemias by examining the progression of this disease in p53 deficient mice. We found that p53-/- mice succumb to the disease more rapidly than p53+/+ littermates. Additionally, of the 112 tumors generated, 19 gave rise to immortal cell lines, eight of which were derived from p53-/- mice, and ten of which were from p53+/- mice. The ability of these primary tumor cells to grow in culture was associated with the complete loss of wild-type p53 in these cell lines. However, cells from many of the tumors induced in p53-/- hosts did not survive in vitro. These results suggest that the loss of p53 does not directly immortalize tumor cells. Instead, we have evidence to suggest that the loss of p53 promotes the accumulation of mutations that are required for survival in culture and that are capable of accelerating tumor progression in vivo. Indeed, mutations causing expression of the growth factor gene erythropoietin (Epo), were detected in two of seven Epo-independent cell lines from p53 deficient primary erythroleukemias. Moreover, the mechanism of activation of the Epo gene in one of these two Epo-independent cell lines involved genomic rearrangement, that is a hallmark of genetic instability. We propose that, in F-MuLV induced-erythroleukemias, p53 loss may encourage the accumulation of further mutations, subsequently conferring a growth advantage and immortality to the transformed erythroblasts.
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PMID:Loss of p53 in F-MuLV induced-erythroleukemias accelerates the acquisition of mutational events that confers immortality and growth factor independence. 1052 29

Consorcial projects focused on 5 cancer types, breast-, colorectal-, head and neck- and pediatric cancers, and malignant melanoma. Breast cancer studies revealed unique splicing mechanisms concerning BRCA1. In sporadic breast cancers the involvement of DNA-repair genes was proved to be dependent on the histological type. Bone-metastatic tumors have been characterized by decreased NM23 and increased c-met and p53 expressions. C-erbB2 genotype of the primary tumor was not maintained frequently in bone metastases. Application of DNA-microarray and quantitative PCR technologies improved the prediction of therapeutic sensitivity of breast cancers. Colorectal cancer studies revealed regional inhomogenities (clusters) in various geographical regions of Hungary, which were distinct in the case of colonic and rectal cancers. To increase the sensitivity of fecal blood test of colorectal cancer screening, a new double-antibody test was developed and tested in a large cohort of patients. Genetic analysis revealed that hypermethylation is a significant factor in microsatellite instability which, and plays a role in silencing of APC and E-cadherin genes as well. The Hungarian pattern of TS polymorphism was also determined and was correlated not only with the efficacy of 5-FU treatment but with the progression of the disease as well. Population-based studies have been carried out in head and neck cancer patients (HNC) and smokers as well to reveal the genetic background of increasing tumor incidence. These studies revealed polymorphism in XRCC1/3 methylation enzyme gene which has preventive role. Other studies found frequent local immunosuppression in HNC patients. Studies indicated that the success of irradiation in this cancer type is dependent on the anti-vascular effects. Pediatric cancer studies determined the parameters of neuroblastoma screening based on VMA measurements. New splice variants of the WT1 gene involved in the monitoring of MRD of ALL patients was also described this year. We also obtained positive experimental data for the retinoic acid therapy of ALL. Melanoma studies extensively used DNA-microarray technology which identified 4 melanoma-specific and 2 melanoma progression-specific genes. In experimental human melanoma xenograft models we have identified 3 anti-metastatic agents: low molecular weight heparin, 2-methoxyestradiol and erythropoietin-alpha, where the later was characterized by specific effects on tumor vasculature.
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PMID:[Report of the National Oncology Research and Developement Consortium, 2003]. 1510

Within the past decade, clinical trials have shown that the presence of anemia can diminish the physical status, functional abilities, and overall quality of life (QOL) of cancer patients and can negatively influence the outcome of their treatment. However, recent preclinical and clinical studies have also shown that increasing hemoglobin levels by administering recombinant human erythropoietin (rHuEPO, epoetin alfa) may ameliorate anemia and, in doing so, improve QOL and possibly result in better treatment outcomes following radiotherapy, chemotherapy, or a combination of these modalities. Several mechanisms by which rHuEPO may improve treatment outcome have been proposed, including correction of tumor hypoxia, increased sensitivity of tumor cells to radiotherapy and chemotherapy, correction of anemia and its associated symptoms (particularly fatigue), and immune-modulated effects of rHuEPO on tumor growth. Improvement of tumor oxygenation by rHuEPO could affect treatment outcome in two ways. First, correction of hypoxia results in the downregulation of hypoxia-inducible factor 1 (HIF-1), a key regulator of cellular adaptive responses to hypoxia (e.g., angiogenesis), including many pathways that are important for tumor growth and metastasis. Interruption of the HIF-1 pathway not only limits growth of the primary tumor but also reduces the potential for the development of more aggressive tumors and metastatic spread, which could ultimately improve treatment outcome. Second, within the tumor, it is the hypoxic cells that are resistant to oxygen-dependent radiotherapy and chemotherapy, and improvement in their oxygenation would increase their sensitivity to the cytotoxic effects of such treatment. Correction of anemia and its associated symptoms, particularly fatigue, can have a beneficial effect on patient QOL, and this in turn may translate into greater tolerance of radiotherapy and chemotherapy, allowing patients to receive full doses and on-schedule dosing, and thus have an increased likelihood of a therapeutic response. Lastly, results of a study using a murine model of multiple myeloma have indicated that rHuEPO may induce an immune-mediated antitumor effect. Therefore, additional research is warranted to further explore the biologic actions of rHuEPO and to determine their relevance to therapeutic outcome.
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PMID:rHuEPO and improved treatment outcomes: potential modes of action. 1559 21

Functional significance of co-expressed erythropoietin (EPO) and its receptor (EPOR) in non-small cell lung cancer (NSCLC) had been under debate. In this study, co-overexpression of EPO/EPOR was confirmed to be positively associated with poor survival in NSCLC. The serum EPO in 14 of 35 enrolled NSCLC patients were found elevated significantly and decreased to normal level after tumor resection. With primary tumor cell culture and patient-derived tumor xenograft (PDX) mouse model, the EPO secretion from the tumors of these 14 patients was verified. Then, we proved the patient derived serum EPO was functionally active and had growth promotion effect in EPO/EPOR overexpressed but not in EPO/EPOR under-expressed NSCLC cells. We also illustrated EPO promoted NSCLC cell proliferation through an EPOR/Jak2/Stat5a/cyclinD1 pathway. In xenograft mouse model, we proved local application of EPO neutralizing antibody and short hairpin RNA (shRNA) against EPOR effectively inhibited the growth of EPO/EPOR overexpressed NSCLC cells and prolonged survivals of the mice. Finally, EPO/EPOR/Jak2/Stat5a/cyclinD1 signaling was found to be a mediator of hypoxia induced growth in EPO/EPOR overexpressed NSCLC. Our results illustrated a subgroup of NSCLC adapt to hypoxia through self-sustainable EPO/EPOR signaling and suggest local blockage of EPO/EPOR as potential therapeutic method in this distinct NSCLC population.
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PMID:Local blockage of self-sustainable erythropoietin signaling suppresses tumor progression in non-small cell lung cancer. 2913 69