Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The records of 46 children treated with ifosfamide between 1987-1994 were analyzed. 24 received the drug as first-line chemotherapy in combination with vincristine and etoposide or with adriamycin, vincristine and cyclophosphamide. Complete remission was achieved in 8/10 children with soft tissue sarcoma, 7/8 with Ewing's sarcoma, 2/2 with ovarian carcinoma and 2/2 with clear cell sarcoma of the kidney. 22 children in whom first-line chemotherapy failed were then treated with ifosfamide and etoposide. Complete remission was achieved in 7/10 children with osteosarcoma, 1/2 with Wilms' tumor and 1/3 with neuroblastoma.
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PMID:[Ifosfamide in pediatric malignancy--experiences in the Northern Israel Oncology Center]. 876 70

WT1 encodes a zinc finger transcription factor that is inactivated in a subset of Wilms' tumors. We have recently shown that introduction of wild-type WT1 into a Wilms' tumor-derived cell line, RM1, results in growth suppression, consistent with its function as a tumor suppressor gene. WT1-mediated growth suppression was also observed in other cells derived from embryonal tumors, including two osteosarcoma cell lines, U2OS and Saos-2, notable for the respective presence or absence of wild-type p53. To further characterize the functional properties of WT1, multiple U2OS and Saos-2 cell lines were established, expressing either wild-type WT1 splicing variants or naturally occurring mutants under control of a tightly regulated tetracycline repressable promoter. Induction of WT1 in these cells resulted in programmed cell death. This effect was preferentially mediated by WT1 isoform B (encoding alternative splice I, lacking alternative splice II "KTS"), and it was independent of p53, occurring in both U2OS and Saos-2 cells. WT1-mediated apoptosis was associated with transcriptional repression of the epidermal growth factor receptor (EGFR) and reduced synthesis of endogenous EGFR protein synthesis. Constitutive expression of EGFR abrogated WT1-mediated cell death. We conclude that wild-type WT1 can induce apoptosis in embryonal cancer cells, presumably through the withdrawal of required growth factor survival signals, and that EGFR is a physiological target gene for WT1.
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PMID:Functional properties of WT1. 882 73

Staging systems are used in staging most pediatric solid tumors outside the central nervous system. Common solid, nonneurologic pediatric tumors include liver tumors, Hodgkin disease, non-Hodgkin lymphoma, Wilms tumor, rhabdomyosarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma. Traditional staging of pediatric tumors depends on the anatomic distribution of the malignant disease. Almost all staging systems are based on the spread of the local primary tumor, metastasis to regional lymph nodes, and distant blood-borne metastatic spread. There is some variability as to how tumor spread is assessed. Such assessment may be performed before or after surgery. There are many potential problems with tumor staging systems. The systems vary in complexity and clinical usefulness, and there is some variation in the criteria used in the different systems. It is important for radiologists to have a sound working knowledge of staging systems to facilitate accurate staging. Imaging is an important aspect of every staging system.
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PMID:Visual presentation of the staging of pediatric solid tumors. 889 21

WT1 encodes a zinc finger transcription factor that is expressed in the developing kidney and the inactivation of which leads to Wilms' tumor, a pediatric kidney cancer. We have recently shown that inducible expression of WT1 in osteosarcoma cells triggers programmed cell death, an effect that is associated with transcriptional repression of the endogenous epidermal growth factor receptor. We now show that WT1-mediated apoptosis is preceded by induction of the cyclin-dependent kinase inhibitor p21, associated with G1 phase arrest. This effect is only demonstrated by WT1 isoforms with an intact DNA binding domain, and it is associated with increased expression of endogenous p21 mRNA. WT1-mediated induction of p21 is independent of p53, another tumor suppressor gene known to regulate p21 expression. In the kidney, p21 is expressed in differentiating glomerular podocytes along with WT1. We conclude that induction of p21 expression may contribute to WT1-dependent differentiation pathways in the kidney and potentially to the function of WT1 as a tumor suppressor gene.
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PMID:Induction of p21 by the Wilms' tumor suppressor gene WT1. 910 40

In the framework of the ITACARE project, a cooperative investigation conducted on the data from the Italian population-based cancer registries, survival of patients with childhood malignant neoplasms was studied. The study included 1,768 cases diagnosed at age 0-14 plus 29 osteosarcoma cases diagnosed at age 15-19. Cases were collected over the period 1978-1989, or more limited periods for some participating registries. A total of 1,138 cases were from the Childhood Cancer Registry of Piedmont and 659 from the registries operating in the provinces of Varese, Parma, Modena, Forli and Ravenna, Florence, Latina, Ragusa and in the cities of Genova and Torino (the last contributed only for bone neoplasm diagnosed at age 15-19). Overall 5-year survival was 54% for malignancies diagnosed in 1978-1981, 60% for the period 1982-1985; and 69% for the period 1986-1989. The range among registries of 5-year survival for cases diagnosed in 1986-1989 was 55-78%. Most diagnostic categories presented an improved prognosis for the cases diagnosed more recently. For cases diagnosed in 1986-1989, 5-year survival was: 74% for acute lymphatic leukaemia, 40% for acute non-lymphatic leukaemia, 65% for central nervous system neoplasms (76% for astrocytoma, 75% for ependymoma and 85% for medulloblastoma), 66% for osteosarcoma, 55% for Ewing's sarcoma, 87% for Hodgkin's disease, 64% for non-Hodgkin's lymphoma, 74% for rhabdomyosarcoma, 64% for neuroblastoma, 78% for nephroblastoma and 100% for retinoblastoma. Italian survival was similar to that observed in other population-based surveys in the UK and USA.
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PMID:Survival of childhood cancer patients in Italy, 1978-1989. ITACARE Working Group. 915 68

In order to investigate the subnuclear interactions of the WT1 gene product, nuclear fractionation analyses were performed with human osteosarcoma HOS and myelogenous leukemia K562 cells. The WT1 protein was tightly associated with the nucleus and was resistant to high-salt or detergent extraction and DNase I digestion. Both the expression level and stability of WT1 and its resistance to high salt and DNase I treatments remained constant during the cell cycle. In addition, human WT1 ectopically expressed in mouse NIH3T3 cells was also resistant to these treatments. These results suggest that WT1 functions in tight association with the nuclear matrix.
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PMID:The Wilms tumor protein is persistently associated with the nuclear matrix throughout the cell cycle. 920 4

The four national paediatric cancer clinical trials organisations in the United States--the Children's Cancer Group, the National Wilms' Tumor Study Group, the Intergroup Rhabdomyosarcoma Study Group and the Pediatric Oncology Group--were formed in 1955, 1969, 1972 and 1979, respectively. Together, the Children's Cancer Group and Pediatric Oncology Group serve as a national registry of nearly all childhood cancers in the United States, provide a national network of communication for researchers, care providers and families of paediatric patients with malignant disease and conduct laboratory investigations and clinical trials of new treatments of cancers in infants, children, adolescents and young adults. Nearly 95% of patients with cancer in the United States who are below 15 years of age are registered by the Children's Cancer Group and the Pediatric Oncology Group and more than half of American children with cancer are entered into at least one trial by a paediatric group. Improved survival of children receiving treatment according to well-defined protocols in specialised children's centres, in contrast to children who received treatment outside of these centres, has been shown for those with acute lymphoblastic leukaemia, lymphoma, Wilms' tumour, medulloblastoma, rhabdomyosarcoma and Ewing's sarcoma. By the year 2000, the overall cure rate for United States children and adolescents with cancer should exceed 85%. To reach this goal, the way forward will depend on international collaboration, implementation of global harmonisation, prevention of the erosion of biomedical research and clinical trials by the managed health care industry, increased public and private financial support and continued recruitment into paediatric oncology of brilliant and dedicated young investigators. The specific challenges ahead include: (1) transferring the knowledge, methodologies and technologies to countries that are less fortunate; (2) conducting multinational clinical trials in conjunction with paediatric cooperative groups in other countries; (3) accessing older adolescent patients who currently do not participate in cooperative group trials; (4) merging clinical trials by adult collaborative groups that overlap with the paediatric groups, as in acute lymphoblastic leukaemia, acute myelogenous leukaemia, Hodgkin's disease, osteosarcoma and germ cell tumours; (5) establishing a stable source of funding for national and international cooperative paediatric cancer clinical trials; (6) creating an informatics system that can link paediatric cooperative group operation centres around the world, and the institutions within each collaborative group; and (7) securing the support of the insurance industry and government in covering clinical trials.
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PMID:The U.S. pediatric cancer clinical trials programmes: international implications and the way forward. 933 87

Chromosomal translocations resulting in chimaeric transcription factors underlie specific malignancies, but few authentic target genes regulated by these fusion proteins have been identified. Desmoplastic small round-cell tumour (DSRT) is a multiphenotypic primitive tumour characterized by massive reactive fibrosis surrounding nests of tumour cells. The t(11;22)(p13;q12) chromosomal translocation that defines DSRT produces a chimaeric protein containing the potential transactivation domain of the Ewing-sarcoma protein (EWS) fused to zinc fingers 2-4 of the Wilms tumour suppressor and transcriptional repressor WT1 (refs 2,3). By analogy with other EWS fusion products, the EWS-WT1 chimaera may encode a transcriptional activator whose target genes overlap with those repressed by WT1 (ref. 4). To characterize its functional properties, we generated osteosarcoma cell lines with tightly regulated inducible expression of EWS-WT1. Expression of EWS-WT1 induced the expression of endogenous platelet-derived growth factor-A (PDGFA), a potent secreted mitogen and chemoattractant whose promoter contains the many potential WT1-binding sites. Native PDGFA was not regulated by wild-type WT1, indicating a difference in target gene specificity between this tumour suppressor and its oncogenic derivative. PDGFA was expressed within tumour cells in primary DSRT specimens, but it was absent in Wilms tumours expressing WT1 and Ewing sarcomas with an EWS-Fli translocation. We conclude that the oncogenic fusion of EWS to WT1 in DSRT results in the induction of PDGFA, a potent fibroblast growth factor that contributes to the characteristic reactive fibrosis associated with this unique tumour.
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PMID:The EWS-WT1 translocation product induces PDGFA in desmoplastic small round-cell tumour. 935 95

Solid malignant tumours (n = 263) excluding brain and spinal cord tumours in children up to 14 years of age were studied. Retinoblastoma (27%) constituted the largest group followed by Wilms' tumour (14.1%) and lymphoma (13.7%). Most patients (55%) were of less than 5 years age and maximum incidence of embryonal tumours was found in this age group; other tumours were more frequent in higher age. A male preponderance was noted (male to female ratio as 1.6:1). Amongst lymphoma, 61% were non-Hodgkin's lymphoma and rest were Hodgkin's disease; 2 cases of Burkitt's lymphoma were found. Other notable tumours encountered in the study were embryonal rhabdomyosarcoma (n = 14), hepatoblastoma (n = 9), neuroblastoma (n = 7), Ewing's sarcoma (n = 21), osteogenic sarcoma (n = 19) and germ cell tumours (n = 14).
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PMID:Pattern of solid malignant tumours in children--a ten-year study. 935 72

WT1 encodes a tumor suppressor that is expressed in cells of the developing kidney and is inactivated in Wilms tumor, a pediatric kidney cancer. The adenovirus E1B 55K gene product contributes to the transformation of primary baby rat kidney (BRK) cells by binding and inactivating the product of the p53 tumor suppressor. We have previously demonstrated that WT1 and p53 are present within a protein complex in vivo. We now show that WT1 is physically associated with E1B 55K in adenovirus-transformed cells, an interaction that is mediated by the first two zinc fingers of WT1. Immunodepletion of p53 abrogates the coimmunoprecipitation of E1B 55K and WT1, consistent with the presence of a trimeric protein complex containing these three proteins. In the presence of E1B 55K, WT1 which is normally localized in the nucleus, is retained within a very high molecular weight complex and sequestered in the characteristic perinuclear cytoplasmic body that contains E1B 55K and p53. Expression of E1B 55K in osteosarcoma cells that undergo apoptosis following expression of WT1 inhibits WT1-mediated cell death. We conclude that E1B 55K may target WT1 along with p53, resulting in the functional inactivation of both tumor suppressor gene products by this viral oncoprotein.
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PMID:E1B 55K sequesters WT1 along with p53 within a cytoplasmic body in adenovirus-transformed kidney cells. 957 85


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