UNIPROT:P04637 - FACTA Search

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)

A 64-year-old-male had recurrent paraaortic lymph node and liver metastases eight months after total gastrectomy and with distal pancreatectomy and splenectomy for advanced gastric cancer. Combined chemotherapy with 5-FU and a low-dose of CDDP was effective and the both lesions disappeared. Thirteen months later, a second recurrence of anterior mediastinum lymph node metastases occurred. After the same protocol, the lesions showed a partial response and lymph node dissection was performed. Histopathological examination showed that the resected lymph nodes had 99% necrosis and fibrotic change. Immunohistochemical examination of p53 of the primary gastric cancer showed negative staining. The patient has been followed for three years after the operation, and has no recurrent lesions.
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PMID:[A case treated successfully with low-dose CDDP and 5-FU for the treatment of liver and para-aortic lymph node metastases and second metastasis to anterior mediastinum lymph nodes from gastric cancer after gastrectomy]. 1204 Jun 80

Drug resistance is often a limiting factor in successful chemotherapy. Our laboratory has been interested in studying mechanisms of resistance to drugs that are targeted to the thymidylate biosynthesis pathway especially those that target thymidylate synthase (TS) and dihydrofolate reductase (DHFR). We have used leukemia as a model system to study resistance to methotrexate (MTX) and colorectal cancer as the model system to study 5-fluorouracil (5-FU) resistance. In leukemias, we and others have shown that transport, efflux, polyglutamylation and hydrolase activities are major determinants of MTX resistance. We have further reported that some leukemic cells have an increase in DHFR gene copy number possibly contributing to the resistant phenotype. Recently, we have begun to study in detail the molecular mechanisms that govern translational regulation of DHFR in response to MTX as an additional resistance mechanism. Studies thus far involving colorectal tumors obtained from patients have focused predominantly on the predictive value of levels of TS expression and p53 mutations in determining response to 5-FU. Although the predictive value of these two measures appears to be significant, given the variety of resistance to 5-FU observed in cell lines, it is not likely that these are the only measures predictive of response or responsible for acquired resistance to this drug. The enzyme uridine-cytidine monophosphate kinase (UMPK) is an essential and rate-limiting enzyme in 5-FU activation while dihydropyrimidine dehydrogenase (DPD) is a catabolic enzyme that inactivates 5-FU. Alterations in UMPK and DPD may therefore explain failure of 5-FU response in the absence of alterations in TS or p53. Transcription factors that regulate TS may also influence drug sensitivity. We have found that mRNA levels of the E2F family of transcription factors correlates with TS message levels and are higher in lung metastases than in liver metastases of colorectal cancers. Moreover, gene copy number of the E2F-1 gene appears to be increased in a significant number of samples obtained from metastases of colorectal cancer. We have also generated mutants of both DHFR and TS that confer resistance to MTX as well as 5-FU by random as well as site-directed mutagenesis. These mutants used alone or as fusion cDNAs of the mutants have proven to be useful in transplant studies where transfer of these mutant cDNAs to bone marrow cells have been shown to confer drug resistance to recipients. The fusion cDNAs of DHFR such as the DHFR-herpes simplex virus type 1 thymidine kinase (HSVTK) are also useful for regulation of gene expression in vivo using MTX as the small molecule regulator that can be monitored by positron emission tomography (PET) scanning or by optical imaging using a fusion construct such as DHFR-EGFP.
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PMID:Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase. 1208 58

p53 suppressor gene mutations are a well known step which occurs in the late stages of the complex tumourigenesis of colorectal cancer. A deregulation of p53 protein function may be associated with increased neovascularization and aggressive tumour growth. In vitro studies have shown that these genetic alterations cause a loss of wild-type p53-induced anti-angiogenetic control and could possibly induce expression of the neoangiogenic vascular endothelial growth factor (VEGF). Therefore, this in vivo study was performed to assess p53 mutations, i.e. hot spots in exons 4-9, in primary colorectal cancers and in corresponding liver metastases in order to test whether there is an association between p53 mutated tumours with increased microvessel density (MVD) and VEGF overexpression. Twenty-two tissue samples taken from primary colorectal cancers and the corresponding liver metastases were immediately snap-frozen in liquid nitrogen and fixed in formaldehyde. After DNA extraction exons 4-9 were amplified and directly sequenced. Cryostat sections were stained immunohistochemically using antibodies against VEGF, CD34, and p53 protein. A modified semiquantitative Weidner score and interactive computerized image analysis was used to assess MVD. Overexpression of immunohistochemically detected p53 protein was found in 7 of the 11 primary tumours and liver metastases (64%). Sequencing showed 3 out of 11 primary tumours (27%) and 5 out of 11 liver metastases (46%) to have p53 point or frameshift mutations; these samples tested immunohistochemically positive for p53 protein. Two p53 mutations in samples of liver metastases were not detectable in the corresponding primaries. We detected one frameshift mutation in exon 4 that has not yet been described in the literature. Tumour samples with p53 mutations and increased VEGF immunoreactivity were associated with higher MVD (p<0.01 and p<0.05, respectively). However, there was no association detected immunohistochemically between p53 and MVD as well as p53 mutations and VEGF overexpression. Our data demonstrate specific genetic alterations in the coding regions of p53 suppressor gene in both primary colorectal cancers and corresponding liver metastases, these alterations are associated with an increase in MVD, but not in VEGF overexpression. In addition, a novel frameshift mutation in both colorectal cancer and metastasis is described.
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PMID:Association of p53 mutations, microvessel density and neoangiogenesis in pairs of colorectal cancers and corresponding liver metastases. 1211 17

To clarify the significance of p53 mutations in liver metastasis of colorectal carcinogenesis, the characteristics of p53 mutations from 51 liver metastases and 76 primary invasive carcinomas without liver metastasis (Dukes' A, B and C) were compared. The frequency of tumors with p53 mutations was 61% (31 out of 51) in the liver metastases, and 51% (39 out of 76) in the primary carcinomas without liver metastasis. Approximately 90% of the informative cases having p53 mutation showed 17pLOH. Mutations detected within exons 4-10 of the p53 gene included missense, nonsense, frameshift, inframe deletion, and inframe insertion mutations. Out of the tumors with p53 mutations, we found that the percentage of tumors with protein-truncating mutations (nonsense and frameshift mutations) was extremely higher in liver metastases (16 out of 31, 52%) than in primary carcinomas without liver metastasis (5 out of 39, 13%) (P=0.0005). The present results suggest that protein-truncating mutations of the p53 gene are more relevant than missense mutations as one of the prognostic factors in liver metastasis of colorectal carcinomas.
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PMID:High incidence of protein-truncating mutations of the p53 gene in liver metastases of colorectal carcinomas. 1224 68

Metastasized neuroendocrine tumors of the gastrointestinal tract and of unknown origin show a highly variable clinical course. Within this group, low-grade and high-grade malignant tumors can be recognized based on the revised classification of neuroendocrine tumors of the lung, pancreas, and gut published by Capella et al in 1995. The present study investigated whether fine-tuning the prediction of prognosis was possible by dividing the group of low-grade malignant tumors of the midgut and of unknown origin into typical and atypical carcinoids by grading them according to the World Health Organization (WHO) classification criteria for neuroendocrine tumors of the lung. Moreover, the prognostic value of immunohistochemical stainings and clinical parameters was evaluated. The study group comprised patients diagnosed between 1983 and 1999 with liver metastases of a neuroendocrine tumor of the midgut n = 40) or of unknown origin (n = 16). As a control for the consistency of grading, 10 patients with metastasized neuroendocrine tumors of the lung also were evaluated. Immunohistochemical stainings for chromogranin A, synaptophysin, Leu 7/CD57, neural cell adhesion molecule/CD56, cytokeratin 8, bcl-2, p53, ki67, and HER2/neu were performed. The clinical parameters age, gender, urinary 5-HIAA level, and presence or absence of the carcinoid syndrome were evaluated. Tumors of the midgut and of unknown origin were evaluated together, because they were clinically similar. In this group of 56 patients, both the Capella and the WHO classification systems recognized the high-grade malignant tumors with a bad prognosis. When the low-grade malignant tumors (Capella) were divided into typical and atypical carcinoids (WHO), no difference in survival was observed, but when the dichotomy into typical and atypical was based on mitotic count alone, the difference became borderline significant (P =.072). Of the immunohistochemical stainings used, synaptophysin, cytokeratin 8, and ki67 had limited prognostic value. Age above 60 was the only clinical parameter of unfavorable prognostic significance. We conclude that high-grade malignant neuroendocrine tumors of the midgut and of unknown origin are recognized by both the Capella classification and the WHO classification of neuroendocrine tumors of the lung. Further subdividing low-grade malignant tumors at this location appears to be of less value than in the lung, but assessing the mitotic activity of these tumors might be of prognostic value.
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PMID:Classification of low-grade neuroendocrine tumors of midgut and unknown origin. 1245 18

Cryotherapy, a method of in situ ablation, is used in the treatment of colorectal liver metastases with variable results. During the treatment, the central area of treated tumor undergoes necrotic destruction by lethal cryo-injury; however, the cellular response of tumor exposed to sublethal cryo-injury at the peripheral zone is unclear. In our study, we have identified the induction of apoptosis by cryo-injury at -10 degrees C in 4 colorectal cancer cell lines (HT29, HCT116, KM12C and KM12SM). The apoptosis was characterized by chromatin condensation, transferase-mediated dUTP nick end-labeling (TUNEL) staining, proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) and cytokeratin 18, and activation of caspase-3. The occurrence and intensity of cryo-induced apoptosis did not correlate with the functional status of p53 in the cell lines studied. The expression of anti-apoptotic proteins (Bcl-2, Bcl-X(L)) and pro-apoptotic proteins (Bax, Bcl-X(S), Bad, and Bak) in response to cryo-injury varied in this cell line panel. The basal level of Bcl-2/Bax protein ratio correlated inversely to the apoptotic rate. We further demonstrated that Bax level decreased in cytosol and increased in mitochondria, followed by a loss of mitochondrial membrane potential after cryo-injury in HT29 cells. These findings indicate that cryo-injury induces apoptosis in colorectal cancer cells via disruption of mitochondrial integrity. The cryo-induced apoptosis was also identified in a nude mouse tumor xenograft model. Our elucidation of the apoptosis pathway induced by cryo-injury implies that synergistic combination of cryosurgery with pharmacological agents that augment of apoptosis induction may have clinical relevance in treating colorectal liver metastasis.
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PMID:Apoptosis induced by cryo-injury in human colorectal cancer cells is associated with mitochondrial dysfunction. 1247 19

To investigate the genetic mechanism of metastatic spread in hepatocellular carcinoma (HCC), we analyzed genomic changes in lung or liver metastases and the corresponding primary tumors (83 tumor samples) in 18 patients who underwent orthotopic liver transplantation. We studied the incidence of microsatellite instability (MSI) and loss of heterozygosity (LOH) involving 8 highly polymorphic microsatellite markers and the polyA tract, Bat26. We also sought alterations of p53 and beta-catenin gene mutations. High MSI (>30-40% of the loci analyzed) was found only in primary tumors (11%), whereas LOH was observed in 50% of primary and in 39% of recurrent tumors. p53 mutations were found in 2 cases of primary HCC but not in the corresponding metastases. P53 was overexpressed in 4 primary HCC (22%) and 7 metastases (39%). The percentage of beta-catenin gene mutations was low (6%). Lung metastases retained the D16S402 microsatellite abnormalities observed in the primary tumors, whereas recurrent liver tumor did not (p = 0.02). In conclusion, LOH and P53 protein overexpression, rather than mutations in the p53 or beta-catenin genes or MSI, seem to be involved in the spreading of HCC, suggesting the presence of metastasis suppressor genes in the vicinity of the chromosomal loci in question.
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PMID:Analysis of chromosomal instability in pulmonary or liver metastases and matched primary hepatocellular carcinoma after orthotopic liver transplantation. 1264 Jun 82

The purpose of this study was (1) to disclose data from a non-randomized trial of prophylactic hepatic arterial chemotherapy for liver metastases from Dukes'C colorectal cancer, (2) to examine the influence of the expression of dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS), and p53 in the primary lesion on this chemotherapy, and (3) to examine the expression of orotate phosphoribosyl transferase (OPRT) mRNA levels in the cases of recurrence included in this study. Patients who underwent curative resection of Dukes'C colorectal cancer between November 1996 and April 2000 were examined. After curative resection, patients were non-randomly divided into two groups after obtaining their informed consent: Hepatic arterial infusion (HAI) group patients (n = 28) were given 5-FU (500 mg/body for 1 h per week, repeated 50 times) via the hepatic artery and peroral UFT-E after resection of Dukes'C colorectal cancer. Control group patients (n = 21) received UFT-E alone. Liver metastasis-free survival did not differ between the groups. Immunohistochemical examinations revealed that the expression of tumoral DPD or p53 was unlikely to affect the hepatic recurrence, although patients with a low expression of TS tended to have better survival in both groups. However, multivariate analysis by the Cox proportional hazard model revealed that a significant prognostic factor influencing the hepatic recurrence is extensive venous invasion. Expression levels of OPRT mRNA, measured in tumors of patients with recurrence (n = 6 for the HAI group; and n = 4 for the control group) were not significantly different between the groups. These results suggest that (1) intermittent hepatic arterial infusion of 5-FU in addition to oral UFT-E was not more useful than administration of UFT alone, and (2) the expression of DPD, TS, p53, and OPRT in the primary lesion was unlikely to affect the prognosis of patients included in this study.
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PMID:[Results of prophylactic hepatic arterial chemotherapy for liver metastases of Dukes C colorectal cancer--correlation with tumoral expression of dihydropyrimidine dehydrogenase, thymidylate synthase, p53, or orotate phosphoribosyl transferase]. 1461 79

We determined the relative value of the metastatic colorectal cancer doubling time as a predictor of recurrence and survival after hepatectomy in comparison with other established predictors. Consecutive patients who underwent hepatic resection ( n = 144) for colorectal cancer liver metastases were studied retrospectively to identify factors that influence overall survival and recurrence in the remnant liver. Overall 5-year survival and nonrecurrence rates were 49.8% and 50.8%, respectively. By multivariate analysis, large liver tumors ( p = 0.038), p53 expression by the liver tumor (p = 0.011), and a short liver metastasis doubling time (< or = 45 days, p = 0.013) negatively affected survival; doubling times > 45 days (adjusted relative risk 0.06; p < 0.001) positively influenced disease-free survival. In patients with remnant liver recurrence, a short doubling time was associated with short disease-free intervals (7.3 +/- 6.2 months), multiple metastases (63.6%), and fewer attempts at repeat hepatectomy (22.7%). The doubling time determines tumor size and reflects the patient's immune and nutritional status. A short doubling time is the most reliable risk factor for multiple metastases, early recurrence, and poor prognosis. Further studies with a larger number of patients are needed to confirm this conclusion.
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PMID:Metastatic tumor doubling time: most important prehepatectomy predictor of survival and nonrecurrence of hepatic colorectal cancer metastasis. 1496 Dec

Antineoplastons work as molecular switches, which regulate expression of genes p53 and p21 through demethylation of promoter sequences and acetylation of histones. They also inhibit the uptake of growth-critical amino acids, such as 1-glutamine and 1-leucine in neoplastic cells. Phase II trials indicate efficacy of antineoplastons in low-grade glioma, brain stem glioma, high-grade glioma, adenocarcinoma of the colon, and hepatocellular carcinoma. The best results were observed in children with low-grade glioma, where 74% of patients obtained objective response, and in patients with adenocarcinoma of the colon with liver metastases whose survival rate of more than 5 years is 91% versus 39% in controls on chemotherapy. Gene array studies will explain antineoplaston-induced changes in gene expression.
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PMID:The present state of antineoplaston research (1). 1531 59

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