Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antibody-based targeted immunotherapy has shown promise as an approach to treat cancer. However, many known tumor-associated antigens are not expressed as integral membrane proteins and cannot be utilized as targets for antibody-based therapeutics. In order to expand the limited target range of antibodies, we have constructed a soluble single-chain T-cell receptor (TCR) fusion protein designated 264scTCR/IL-2. This fusion protein is comprised of a three-domain HLA-A2-restricted TCR specific for a peptide epitope of the human p53 tumor suppressor protein, which is overexpressed in a broad range of human malignancies. The 264scTCR/IL-2 fusion protein has been expressed at high levels in mammalian cells, and milligram quantities have been purified. MHC-restricted antigen-specific binding properties are maintained in the single-chain, three-domain TCR portion of the fusion protein, and the IL-2 portion retains bioactivity similar to that of free recombinant IL-2. Moreover, this fusion protein is capable of conjugating target and effector cells, remains intact in the blood and substantially increases the half life of the IL-2 portion of the molecule. Finally, the 264scTCR/IL-2 fusion protein can be used to stain tumor cells and is capable of reducing lung metastases in an experimental model of metastasis. Thus, TCR-based fusion proteins may provide a novel class of targeted immunotherapeutics for cancer.
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PMID:A soluble single-chain T-cell receptor IL-2 fusion protein retains MHC-restricted peptide specificity and IL-2 bioactivity. 1461 Jun 21

New promising compounds, derived from the esterification of hyaluronic acid with butyric acid, were investigated in vitro on a non-small cell lung carcinoma cell line (NCI-H460) and an its metastatic subclone (NCI-H460M). All new compounds exerted a dose-dependent inhibitory effect on both cell lines, which expressed CD44, the specific surface receptor for hyaluronic acid, in a very high percentage of cells (90%). HE1, the most effective of these compounds, was 10-fold more effective than sodium butyrate (NaB) in inhibiting cell proliferation. Similarly to NaB, after 24 hours of treatment, HE1 affected the expression of three cell cycle-related proteins (p27(kip1), p53 and p21(waf1)) responsible for growth arrest, indicating that the presence of the hyaluronic acid backbone does not interfere with the biologic activity. Intratumoral treatment with HE1 demonstrated a marked efficacy on primary tumor growth and on lung metastases formation of the murine Lewis Lung Carcinoma model. Altogether, present findings suggest a possible clinical application of these novel butyric pro-drugs in primary and metastatic lung cancer.
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PMID:Hyaluronic-acid butyric esters as promising antineoplastic agents in human lung carcinoma: a preclinical study. 1512 68

We describe a case history of a 24-year-old male with osteogenesis imperfecta (OI) who developed osteosarcoma of the left thigh. High-dose ifosfamide therapy caused marked tumor regression of multiple lung metastases. Immunohistochemically, the tumor cells were diffusely positive for the p53 protein. Mutation of the p53 gene was not detected by direct genomic sequencing of exons 4-8. The radiographic characteristics, including irregularly distributed osteolytic lesions and cortical discontinuity, should not be confused with hyperplastic callus formation, a benign process. A biopsy is critical to establish the differential diagnosis between osteosarcoma and common hyperplastic callus formation in OI; however, it must be applied with great care.
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PMID:Osteosarcoma occurring in osteogenesis imperfecta. 1521 33

BBR3464, a novel tri-nuclear platinum complex, forms long-range DNA adducts and is highly potent when compared with cisplatin in vitro. Preclinical studies demonstrated activity in cisplatin-resistant tumours and tumours with mutated p53 status. Phase I & II clinical studies gave preliminary indications of activity in melanoma, pancreatic, lung and ovarian cancers. The aim of this study was to determine the efficacy and confirm the toxicity of BBR3464 when given either as first- or second-line treatment for advanced disease in patients with gastric and gastro-oesphageal adenocarcinoma. Two multicentre, open label, Gehan design studies were conducted; one study used BBR3464 as first-line and the other as second-line treatment for metastatic or locally advanced disease. Nineteen first-line and 26 second-line patients were enrolled receiving a total of 74 and 53 infusions, respectively. Initially, seven patients in the second-line study received BBR3464 using the planned schedule of 1.1 mg/m2 every 4 weeks; however, 5 of these patients experienced dose-limiting grade 3 or 4 febrile neutropenia; subsequent patients in both studies were treated using the modified schedule of 0.9 mg/m2, every 21 days. In 1 of 17 evaluable, previously untreated patients, regression of multiple skin lesions was noted with stabilisation of lung metastases and maxillary sinus mass, lasting 155 days. In the first-line study, the median time to progression was 85 days [95% Confidence Interval (CI): 42, 127] (2.8 months) and in the second-line study, the median time to progression was 71 days [95% CI: 42, 109] and 38 days [95% CI: 32, 73] in the 1.1 and 0.9 mg/m2 dose level groups, respectively. Toxicity data were available for 45 patients. Neutropenia was the main toxicity seen (G3: 40%, G4: 40%). Febrile neutropenia was observed in six patients (15%) treated with 0.9 mg/m2 compared with five patients (71%) treated with 1.1 mg/m2 BBR3464. Other drug-related toxicities (G3/4) included: anaemia, thrombocytopenia, nausea, vomiting, diarrhoea, mucositis and fatigue. Diarrhoea and nausea/ vomiting were adequately controlled by the use of loperamide and antiemetics, respectively. Recruitment to the second-line study was closed early due to the poor response rate (1/17 evaluable, 6%; 95% CI: 1%, 27%) and short time to progression noted in the first-line study. Further studies with BBR3464 in this tumour type are not recommended.
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PMID:Phase II studies of BBR3464, a novel tri-nuclear platinum complex, in patients with gastric or gastro-oesophageal adenocarcinoma. 1528 89

The status of microsatellite markers located on chromosomes 1p36, 3p25, 5q23, 9p22, 10q23, 10q24, 17p13, and 19q12 was used to determine loss of heterozygosity (LOH) in primary giant cell tumors (GCT) of bone in 12 patients. The cases included primary, locally recurrent, and metastatic GCT; three tumors were classified as malignant GCT, based on their morphological features. Microdissection was performed on 24 paraffin-embedded tissue samples. An average of three separate topographic sites were microdissected from each tumor. Case selection in each instance was based on the availability of paired samples of tumor in primary GCTs and their corresponding recurrences, and the presence of normal tissue. The number of cases studied is too small for statistical studies, and thus the analysis is descriptive. All cases were informative for >80% of the markers used. Both primary GCTs and local recurrences and lung metastases displayed LOH of three or more markers, and intratumoral heterogeneity was frequent. Fractional allelic losses (FAL) were not different in recurrent and nonrecurrent GCT. FAL was greatest (>30%) in the metastatic group of GCT. Allelic losses of 1p, 9q, and 19q regions were frequent in all groups. LOH of 17p (in proximity to the p53 locus) and 9p occurred exclusively in the pulmonary metastases from GCT. LOH of 9q and 19q was present in primary as well as recurrent GCTs and in one malignant GCT. Involvement of 1p (including MYCL) and 9q regions has not been previously reported in GCT of bone. The pattern of LOH evident in the 17 markers used in the present study suggests that GCT with malignant features may follow an evolutionary pathway similar to the usual primary GCT of bone.
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PMID:Molecular analysis of primary and recurrent giant cell tumors of bone. 1579 59

Based on previous studies, a minimal set of genetic alterations that is required to convert normal human fibroblasts into cancer cells has been defined. Essential roles for telomere maintenance and alterations in phosphatase 2A activity were inferred from experiments in which tumorigenicity was tested by injecting cells under the skin of immunodeficient mice. However, in the present experiments, the combination of SV40 large T antigen and activated Ras, without hTERT or SV40 small t antigen, was sufficient to convert nine different primary human fibroblast cell strains to a fully malignant state. The malignant behavior of the cells was demonstrated by growth of the cells into invasive tumors when the cells were injected beneath the kidney capsule of immunodeficient mice. Lung metastases and circulating tumor cells were also detected. These tumors were not immortal; cells entered crisis, from which they could be rescued by expression of hTERT. However, the same cell populations were not tumorigenic when they were injected under the skin. In this site, tumorigenicity required the expression of hTERT and SV40 small t antigen as well as SV40 large T antigen and Ras. The cellular pathways targeted by SV40 large T antigen (p53 and pRb) and those targeted by activated Ras represent a minimal set of genetic alterations required for the conversion of normal human fibroblasts into cancer cells.
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PMID:The minimal set of genetic alterations required for conversion of primary human fibroblasts to cancer cells in the subrenal capsule assay. 1603 9

In this study, we investigated the suppressive effect of a short hairpin RNA delivered by a lentiviral vector (LV-shRNA) against human papillomavirus (HPV) type 18 E6 on the expression of the oncogenes E6 and E7 in cervical cancer HeLa cells both in vitro and in vivo. The LV-shRNA effectively delivered the shRNA to HeLa cells and lead to a dose-dependent reduction of E7 protein and the stabilization of E6 target proteins, p53 and p21. Low-dose infection of HeLa cells with LV-shRNA caused reduced cell growth and the induction of senescence, whereas a high-dose infection resulted in specific cell death via apoptosis. Transplant of HeLa cells infected with a low dose of LV-shRNA into Rag-/- mice significantly reduced the tumor weight, whereas transplant of cells infected with a high dose resulted in a complete loss of tumor growth. Systemic delivery of LV-shRNA into mice with established HeLa cell lung metastases led to a significant reduction in the number of tumor nodules. Our data collectively suggest that lentiviral delivery is an effective way to achieve stable suppression of E6/E7 oncogene expression and induce inhibition of tumor growth both in vitro and in vivo. These results encourage further investigation of this form of RNA interference as a promising treatment for cervical cancer.
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PMID:Inhibition of cervical cancer cell growth in vitro and in vivo with lentiviral-vector delivered short hairpin RNA targeting human papillomavirus E6 and E7 oncogenes. 1681 Mar 14

Familial osteosarcoma is a rare hereditary disease. We present a 37-year-old father and a 17-year-old son who developed osteosarcoma in the left and right distal femurs, respectively, at a three-year interval. They were treated with chemotherapy followed by surgery. Both had positive immunostaining for p53 tumor suppressor gene and HER-2/neu oncogene. The son also exhibited deletion of the retinoblastoma 1 gene. Pulmonary metastasis was detected in the father at the time of diagnosis and 13 months after primary treatment, whereas no distant metastasis was present in the child. The father died 39 months after the diagnosis from primary symptoms, but the son led a disease-free survival a year after completion of treatment. Genetic abnormalities documented in the father and son corroborate the presence of specific genetic alterations in the pathogenesis of osteosarcoma.
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PMID:[An analysis of genetic transmission in a father and son with osteosarcoma]. 1722 Jun 52

Giant cell tumor is a benign but locally aggressive tumor that primarily affects the epiphyses of long bones of young adults. Pulmonary metastases in giant cell tumor are rare (about 1-9%). Here, we report a case of metastatic pulmonary giant cell tumor in a patient who had a previous history of giant cell tumor of the distal femur with multiple recurrences. The diagnosis of pulmonary metastasis was achieved by cytologic evaluation with concurrent immunohistochemical studies in material obtained by fine-needle aspiration biopsy. The aspirate smears contained clustered and dispersed mononuclear and osteoclast-like giant cells that had bland nuclei with inconspicuous nucleoli. All multinucleated cells showed immunoreactivity to KP-1 antibody, a histiocytic marker (not lineage specific) and only a subset of mononuclear cells (30%) stained with this marker. Twenty percent of the mononuclear cells also displayed increased Ki-67 and p53 protein expression. The pulmonary metastasis was similar morphologically and immunophenotypically to the recurrent giant cell tumor of the bone.
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PMID:Pulmonary metastasis of giant cell tumor of the bone diagnosed by fine-needle aspiration biopsy. 1749 58

In this study, we establish an MCF-7 xenograft model that mimics the progression of human breast carcinomas typified by loss of p53 integrity, development of centrosome amplification, acquired estrogen receptor (ERalpha) heterogeneity, overexpression of Mdm2 and metastatic spread from the primary tumor to distant organs. MCF-7 cells with abrogated p53 function (vMCF-7(Dnp53)) maintained nuclear ERalpha expression and normal centrosome characteristics in vitro. However, following mitogen stimulation, they developed centrosome amplification and a higher frequency of aberrant mitotic spindles. Centrosome amplification was dependent on cdk2/cyclin activity since treatment with the small molecule inhibitor SU9516 suppressed centriole reduplication. In contrast to the parental MCF-7 cells, when introduced into nude mice as xenografts, tumors derived from the vMCF-7(DNp53) cell line developed a strikingly altered phenotype characterized by increased tumor growth, higher tumor histopathology grade, centrosome amplification, loss of nuclear ERalpha expression, increased expression of Mdm-2 oncoprotein and resistance to the antiestrogen tamoxifen. Importantly, while MCF-7 xenografts did not develop distant metastases, primary tumors derived from vMCF-7(DNp53) cells gave rise to lung metastases. Taken together, these observations indicate that abrogation of p53 function and consequent deregulation of the G1/S cell cycle transition leads to centrosome amplification responsible for breast cancer progression.
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PMID:Impaired p53 function leads to centrosome amplification, acquired ERalpha phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts. 1826 35


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