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)

5-Fluorouracil (5FU)-based therapy is given to patients with advanced colorectal cancer and as adjuvant treatment. Thymidylate synthase (TS) is the target for 5FU, and may have a prognostic role for the outcome of 5FU-based therapy together with proliferation markers such as p53 and Ki67. Thymidine phosphorylase (TP, also known as platelet-derived endothelial cell growth factor) may be of importance both in the 5FU drug activation pathway and in tumor angiogenesis, similar to vascular endothelial growth factor (VEGF). TS and TP levels were determined biochemically in fresh-frozen tumor specimens of 32 untreated patients with colorectal cancer, whereas in paraffin-embedded tissue samples, immunohistochemistry was performed for TS, TP, and additional prognostic markers such as p53, Ki67, and VEGF as well as microvessel density. All factors were correlated with patient characteristics such as age, gender, Dukes' stage, angio-invasion, and differentiation grade. TS and TP as measured by various assays were correlated with overall and disease-free survival in this patient group. TP enzyme activity and protein expression correlated with each other. A significant correlation was found between TP enzyme activity and 5-fluoro-2'-deoxyuridine-5'-monophosphate binding activity. VEGF expression correlated significantly with TP immunostaining and Ki67 index. Survival analysis revealed a significant relation of TS levels to the overall survival in this small patient group and a significant correlation between TP activity and disease-free survival. TS and TP both were of prognostic significance in these patients with colorectal cancer. The interesting relationship of TS and TP with angiogenesis and proliferation needs further investigation.
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PMID:Prognostic role of thymidylate synthase, thymidine phosphorylase/platelet-derived endothelial cell growth factor, and proliferation markers in colorectal cancer. 1074 35

Thymidine phosphorylase (TP) has been implicated as a potent angiogenic factor and a prognostic factor in various human solid tumors. We investigated the expression of TP in a series of human astrocytic tumors using immunohistochemistry, enzyme-linked immunosorbent assay, and reverse transcriptase/polymerase chain reaction (RT-PCR) analysis. A total of 63 astrocytic tumors [27 glioblastomas (GBM), 19 anaplastic astrocytomas (AA), 17 low-grade astrocytomas (LGA)] and 5 normal brain tissues were immunohistochemically stained with antibodies to TP, vascular endothelial growth factor (VEGF), p53, MIB-1, and factor-VIII-related antigen. They were also evaluated for the degree of apoptosis by a ApopTag kit. Ten tumors (5 GBM, 2 AA, 3 LGA) and 3 normal brain tissues were evaluated for their expression of VEGF and TP by RT-PCR analysis. TP was constantly localized in the cytoplasm of astrocytic tumor cells, less intensely in the cytoplasm of vascular endothelial cells, but not in the normal brain. Some of the TP-positive cells were of macrophage origin, but most positive cells were the tumor cells themselves. Vascular density, MIB-1 positivity, p53 positivity, VEGF expression, and the apoptotic index were significantly higher in the TP-positive tumors than in TP-negative tumors. There was a significant correlation between TP and VEGF mRNA expression. In a limited number of glioblastoma cases, the apoptotic index was significantly higher in TP-positive glioblastomas than in TP-negative glioblastomas. In human astrocytic tumors, TP was expressed in the tumor, macrophage, and endothelial cells. TP was a potent angiogenic factor closely associated with cell proliferation and tumor apoptosis.
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PMID:Expression of the angiogenic factor thymidine phosphorylase in human astrocytic tumors. 1074 8

The nuclear area (NA) of cancer cells have been reported to be a useful prognostic indicator in various tumors. However, this image analysis of cancer nucleus has only rarely been applied to gastric adenocarcinoma. Moreover, it remains to be shown what types of biological factors influence this nuclear feature. In this study, we analyzed the area of cancer nuclei in tumors from 97 patients with advanced gastric cancer (t3, n0, stage II) by using hematoxylin and eosin stained slides with a computer-assisted image-analysis system. The morphometric data were compared with clinicopathological and biological status of the tumors. The mean NA of 50 tumors with venous invasion (50 microm2) was significantly larger than that of 47 tumors without venous invasion (38 microm2, p<0.0001). There was a significant correlation between the NAs of cancer cells and the p53 labeling indices of tumors (p=0.0012) and Ki-67 labeling indices of tumors (p=0.0324). However, no significant correlation was detected between the NAs of cancer cells and other factors, such as, tumor size, DNA ploidy pattern, expression of vascular endothelial growth factor (VEGF), or microvessel density of tumors. The five-year survival rate of 49 patients with large nuclear area (NA > or =41 microm2, 63%) was significantly lower than that of 48 patients with small nuclear area (NA <41 microm2, 78%, p=0.043). Data from computerized morphometry are objective and can be obtained rapidly by conventional microscopic analysis. The NA of cancer cells in advanced gastric cancer appears to predict the ability to invade the microvessels in the gastric wall. This nuclear morphological feature strongly correlated with p53 accumulation in the nuclei of gastric adenocarcinoma.
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PMID:Nuclear accumulation of p53 protein in gastric cancer strongly correlates with enlargement of nuclear area of cancer cells. 1076 71

There is a need for the development of reliable tumor markers in bladder cancer. A number of studies this past year focused on the evaluation of urinary markers that hold promise as noninvasive adjuncts to traditional diagnostic or surveillance techniques, principally urinary cytology and cystoscopy. Tests for bladder tumor antigen, NMP22, and fibrin degradation products, as well as the Immunocyt test, are commercially available. Other urinary marker tests discussed in this review include telomerase, cytokeratins, and vascular endothelial growth factor. Although these tests in many instances have improved sensitivity in detecting bladder cancer compared with urinary cytology, none have become widely accepted in routine clinical practice. Nonetheless, with further refinement and prospective validation in multicenter trials, markers such as these may provide information that would permit tailoring on an individual basis the type of as well as interval of surveillance examinations. Furthermore, they may also provide information allowing the appropriate selection of therapy based on predicted response. In addition to urinary markers, intense research efforts have also focused on developing clinically useful molecular prognostic markers. A number of cell-cycle regulatory proteins, including p53 and p21, have received much attention in this regard. Emerging data suggests that it may soon be possible to determine the molecular phenotype of both superficial and invasive bladder cancers, thereby providing information regarding tumor behavior on an individual basis. As with urinary markers, however, no molecular markers have been incorporated as yet into day-to-day patient care. Assurances of reproducibility, standardization, and prospective validation studies are urgently needed. It is only through this type of rigorous evaluation that the level of confidence sufficient to base treatment decisions on marker status will be attained.
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PMID:Bladder cancer. 1084 Nov 98

Tumour angiogenesis has been recently recognised as one of the most important prognostic factors in lung cancer. Although a variety of angiogenic factors have been identified, the angiogenesis process remains poorly understood. Bcl-2, c-erbB-2 and p53 are well-known oncogenes involved in non-small-cell lung cancer pathogenesis. A direct correlation of thymidine phosphorylase (TP) and of vascular endothelial growth factor (VEGF) with intratumoural angiogenesis has been reported. In the present study we investigated the possible regulatory role of bcl-2, c-erB-2 proteins in angiogenesis and in VEGF and TP expression in non-small-cell lung cancer. Two hundred sixteen specimens from T1,2-N0,1 staged patients treated with surgery alone were immunohistochemically examined. Bcl-2 and c-erbB-2 were significantly inversely related to each other (P = 0.04) and both were inversely associated with microvessel density (P < 0.02). High TP and VEGF reactivity was statistically related to loss of bcl-2 expression (P < 0.01). A significant co-expression of c-erbB-2 with TP was noted (P = 0.01). However, TP expression was related to high angiogenesis only in cases with absence of c-erB-2 expression (P < 0.0001). c-erbB-2 expression in poorly vascularised tumours was linked with poor outcome (P = 0.03). The present study provides strong evidence that the bcl-2 gene has a suppressive function over genes involved in both angiogenesis (VEGF and TP) and cell migration (c-erbB-2) in NSCLC. TP and c-erbB-2 proteins are significantly, and often simultaneously, expressed in bcl-2 negative cases. However, expression of the c-erbB-2 abolishes the TP-related angiogenic activity. Whether this is a result of a direct activity of the c-erbB-2 protein or a consequence of a c-erbB-2-related immune response remains to be further investigated.
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PMID:bcl-2 and c-erbB-2 proteins are involved in the regulation of VEGF and of thymidine phosphorylase angiogenic activity in non-small-cell lung cancer. 1084 53

We examined the clinical and pathological significance of thymidine phosphorylase (dThdPase) and vascular endothelial growth factor (VEGF) in human gastric carcinomas, in terms of intratumoral microvessel density (IMVD), P53 expression, and patient prognosis in a total of 128 patients. Mean IMVD was significantly higher in the carcinomas with dThdPase or VEGF expression than in carcinomas without the expression. The simultaneous expression of dThdPase and VEGF was correlated with increased IMVD of human gastric carcinomas. VEGF expression was associated with P53 expression and poor patient prognosis, but dThdPase expression was not.
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PMID:Expressions of thymidine phosphorylase (dThdPase) and vascular endothelial growth factor on angiogenesis in intestinal-type gastric carcinoma. 1085 53

Our recent studies (R. Pollock et al., Clin. Cancer Res., 4: 1985-1994, 1998; M. Milas et al., Cancer Gene Ther., in press, 2000) have shown that the restoration of wild-type (wt) p53 enhances cell cycle control in vitro and inhibits the growth of human soft-tissue sarcoma in severe combined immunodeficient mice. We hypothesized that the antitumor effect of wt p53 overexpression in sarcoma cells is attributable not only to enhanced cell cycle control but also to inhibition of angiogenesis. We evaluated the effect of restoring wt p53 function on angiogenesis in human soft-tissue sarcoma harboring mutant p53. Restoration of wt p53 expression in human leiomyosarcoma SKLMS-1 cells that contain mutant p53 markedly inhibited angiogenesis induced by tumor cells in vivo. Angiogenesis assays using an in vivo Matrigel plug assay demonstrated that less neovascularization in severe combined immunodeficient mice was observed with conditioned medium (CM) from human synovial sarcoma cells expressing wt p53 compared with CM from human synovial sarcoma cells expressing mutant p53. Microvessel density and microvessel counts were lower in tumor xenografts from cells containing wt p53 than in tumor xenografts from cells containing mutant p53. The growth and migration of murine lung endothelial cells were decreased when cells were treated with CM from sarcoma cells expressing wt p53 compared with CM from sarcoma cells expressing mutant p53. The introduction of wt p53 into sarcoma cells containing mutant p53 significantly reduced the expression of vascular endothelial growth factor (VEGF), which is a key mediator of tumor angiogenesis. Stimulation of endothelial cell migration by CM from cells expressing mutant p53 was significantly reduced after anti-VEGF neutralizing antibody was added to the CM. Using luciferase as the reporter of VEGF promoter activity, we found that wt p53 inhibited VEGF promoter activity in SKLMS-1 cells. Deletion analysis defined an 87-bp region (bp -135 to -48) in the VEGF promoter that is necessary for inhibiting VEGF promoter activity by wt p53. The transcription factor Sp1 may be involved in the repression of VEGF promoter activity by wt p53 in SKLMS-1 cells. These data indicated that wt p53 can suppress angiogenesis in human soft-tissue sarcomas by transcriptional repression of VEGF expression.
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PMID:Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. 1091 82

Tumor angiogenesis, the development of new blood vessels during malignant progression, is a regulated process that has both genetic and physiological controls. Physiologically, angiogenesis is stimulated by decreases in tissue oxygenation (i.e., hypoxia). We investigated the effect of hypoxia on the expression of two angiogenic factors reported to be genetically regulated by the p53 tumor suppressor gene: (a) the angiogenic inhibitor thrombospondin 1 (TSP-1); and (b) the angiogenic inducer vascular endothelial growth factor (VEGF). Analysis of rodent cells that differ in their p53 genotype (p53+/+ or p53-/-) indicated that in vitro exposure to hypoxia simultaneously suppressed TSP-1 and induced VEGF expression, regardless of the p53 genotype. On transformation of these cells with E1A and oncogenic H-ras, the basal level of TSP-1 expression was strongly diminished, whereas that of VEGF could still be induced by hypoxia. Consistent with these in vitro findings, sections of tumors derived from the transformed p53+/+ and p53-/- cells showed that VEGF protein overlapped with regions of hypoxia, whereas TSP-1 protein was below the limits of detection in tumor tissue. Using a panel of normal/immortalized and transformed human cells, it was found that the ability of hypoxia to inhibit TSP-1 expression depends on the cell type and/or the degree of transformation. In contrast, VEGF expression was induced by hypoxia in all of the human cell types examined. Together, these findings suggest that hypoxic and oncogenic signals could interact in the tumor microenvironment to inhibit TSP-1 and induce VEGF expression, promoting the switch to the angiogenic phenotype.
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PMID:Opposing effects of hypoxia on expression of the angiogenic inhibitor thrombospondin 1 and the angiogenic inducer vascular endothelial growth factor. 1091 44

Recently, p73, a new member of the p53 family, has been cloned and mapped to chromosome 1p36, a region that is frequently deleted in a variety of human cancers. p73 can activate p53-responsive promoters and induce apoptosis when overexpressed in certain p53-deficient tumor cells. In contrast to p53, analysis of the p73 gene in several human solid tumors did not reveal loss of p73 expression or mutations in the p73 gene. However, transcriptional silencing of the p73 gene by hypermethylation of a CpG island was observed in several leukemias and lymphomas. These lymphoid neoplasms also show increased expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a key mediator of angiogenesis. To evaluate a possible relationship between p73 status and VEGF expression, we have studied the effect of ectopically expressed p73 on the regulation of the VEGF gene. Our results demonstrate that p73 can down-regulate endogenous VEGF gene expression on mRNA and protein level. This effect is mediated by transcriptional repression of the VEGF promoter and involves the promoter region -85 to -50 bp, containing a cluster of Sp 1 binding sites. Our results suggest a regulatory role for p73 in tumor angiogenesis. Oncogene (2000) 19, 3470 - 3476
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PMID:Expression of the vascular endothelial growth factor gene is inhibited by p73. 1091 5

Angiogenesis is required for the growth and progression of malignancies. Recent studies have demonstrated that genetic alterations may accompany acquisition of the angiogenic phenotype. Here we demonstrate that the recombinant adenovirus-mediated transfer of the wild-type p53 gene into a mutant p53-expressing human non-small cell lung cancer cell line markedly inhibited the expression of an angiogenic factor, vascular endothelial growth factor (VEGF), and increased the expression of a novel antiangiogenic factor, brain-specific angiogenesis inhibitor 1 (BAI 1), resulting in reduced neovascularization in vivo. These results may explain in part the mechanism of the bystander effect induced by wild-type p53 gene transfer of adjacent tumor cells.
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PMID:[Recombinant adenovirus expressing wild-type p53 is antiagiogenic--implication for lung cancer gene therapy]. 1094 20


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