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)

The comparative typing of matched tumor and blood DNAs at dinucleotide repeat (microsatellite) loci has revealed in tumor DNA the presence of alleles that are not observed in normal DNA. The occurrence of these additional alleles is possibly due to replication errors (RERs). Although this observation has led to the recognition of a subtype of colorectal cancer with a high incidence of RERs (caused by a deficiency in DNA mismatch repair), a thorough analysis of the RER frequency in a consecutive series of colorectal cancers had not been reported. It is shown here that the extensive typing of 88 colorectal tumors reveals a bimodal distribution for the frequency of RER at microsatellite loci. Within the major mode (75 tumors, RER- subtype), the probability that a locus exhibited instability did not differ significantly among loci and tumors, being 0.02. The subsequent development of a statistical test for an operational discrimination between the RER- and RER+ subtypes indicated that the probability of misclassification did not exceed 0.001 in this series. The frequency of K-ras mutation was found to be equivalent in the two subtypes. However, in the RER+ tumors, the p53 gene mutation was less frequently detected, the adenomatous polyposis coli (APC) mutation was rare, and the biallelic inactivation of either of these genes was not observed. Furthermore, the concomitant occurrence of APC and tumor growth factor beta receptor type II gene alterations was found only once. These data suggest that the repertoires of genes that are frequently altered in RER+ and RER- tumors may be more different than previously thought.
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PMID:Alternative genetic pathways in colorectal carcinogenesis. 934 73

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Five-fluorouracil (5FU) remains the single most effective treatment for advanced disease, despite a response rate of only 20%. Herein, we show that the antioxidants pyrrolidinedithiocarbamate and vitamin E induce apoptosis in CRC cells. This effect is mediated by induction of p21WAF1/CIP1, a powerful inhibitor of the cell cycle, through a mechanism involving C/EBPbeta (a member of the CCAAT/enhancer binding protein family of transcription factors), independent of p53. Antioxidants significantly enhance CRC tumor growth inhibition by cytotoxic chemotherapy in vitro (5FU and doxorubicin) and in vivo (5FU). Thus, chemotherapeutic agents administered in the presence of antioxidants may provide a novel therapy for colorectal cancer.
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PMID:Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21WAF1/CIP1 via C/EBPbeta. 935 86

In this study we investigated the immunohistochemical expression of the p53 protein in 44 ductal pancreatic adenocarcinomas and its relation to cell proliferation, apoptosis and necrosis, three factors affecting tumor growth. The results were evaluated against survival and other clinical parameters of the patients. p53-positivity was found in 18/44 (41%) of the tumors. A positive p53 status was significantly associated with a high extent of necrosis (> or = 10% of tumor tissue)(p = 0.04, Fisher's exact test), with a high immunohistochemical expression of PCNA (p = 0.04, Fisher's exact test) and with a high mitotic count (p = 0.05, two-tailed t test). No statistically significant association was found between p53-positivity and high or low extent of apoptosis as evaluated by in situ labeling of the 3'-ends of the DNA fragments (p = 0.34, Fisher's exact test). Patient survival was not associated with the p53 expression of the tumors or separately with tumor cell proliferation, apoptosis or necrosis. The results suggest that an altered p53 function, as reflected by p53 overexpression, affects tumor growth by promoting cell proliferation and necrosis, but does not show a significant association with the extent of apoptosis in operated pancreatic adenocarcinoma.
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PMID:Association between p53 overexpression, cell proliferation, tumor necrosis and extent of apoptosis in operated pancreatic adenocarcinoma. 936 91

In this study, the inhibitory effect of Yifei Kangliu Yin (YFKL) was observed on growth of LAX-83 human lung adenocarcinoma in naked mice. It was found that the YFKL could suppress the tumor growth significantly with a suppression rate of 45.59%. It was also found that positive expression of Ki-67 and cell proliferation significantly decreased, c-myc changed from positive to weak positive and P53 from positive to negative in the YFKL treated group. It suggested that the inhibitory effect of YFKL on proliferation of cancer cells might be realized by way of changing the oncogenetic expression of cancer, so as to influence the cell proliferation directly.
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PMID:[Experimental study on inhibitory effect of yifei kangliu decoction on cell proliferation in lung cancer]. 938 51

Our laboratory has developed two cellular models of human prostate cancer progression. The LNCaP prostate cancer progression model is based upon the well-known cellular interaction between human prostate or bone stromal cells and LNCaP cells in vivo. The marginally tumorigenic LNCaP cells acquired tumorigenic and metastatic potential upon cellular interaction with either prostate or bone fibroblasts. A subline termed C4-2 was observed to grow readily in castrated animals and acquired metastatic potential spreading from the primary tumor site to the lymph node, the seminal vesicles, and the axial skeleton, resulting in an intense osteoblastic reaction. The second model is ARCaP, where prostate cancer cells derived from the ascites fluid of a man with metastatic disease exhibited an Androgen- and estrogen-Repressed Prostate Cancer cell growth and tumor formation in either a hormone-deficient or a castrated environment. However, the growth of either the tumor cells in vitro or the tumors in vivo was suppressed by both estrogen and androgen. While the tumor cells expressed low levels of androgen receptor and prostate-specific antigen (PSA), they were highly metastatic when inoculated orthotopically. Distant metastases to a number of organs were detected, including the liver, lung, kidney, and bone. We have employed a human prostate cancer progression model as a system to study the efficacy of gene therapy. Results of the study show that whereas universal promoters, such as Cytomegalovirus (CMV) and Rous Sarcoma Virus (RSV) promoter-driven tumor suppressors (e.g. p53, p21, and p16), were effective in inhibiting prostate tumor growth, the advantages of driving the expression of therapeutic toxic genes using a tissue-specific promoter prostate-specific antigen (PSA) and a tumor--but not tissue-specific promoter, osteocalcin (OC), are preferred. In the case of the PSA promoter, we can achieve cell-kill in PSA-producing human prostate cancer cells. To circumvent the supporting role of bone stroma for prostate cancer epithelial growth, we have recently developed a novel concept where the expression of therapeutic toxic genes is driven by a tumor--but not a tissue-specific OC promoter. Osteocalcin-thymidine kinase (OC-TK) was found to efficiently eradicate the growth of osteosarcoma, prostate, and brain tumors both in vitro and in vivo. We observed that androgen-independent human prostate cancer cells lines expressed OC-TK at higher levels than androgen-dependent human prostate cancer cell lines. We have obtained data to suggest that Ad-OC-TK plus a pro-drug acyclovir (ACV) may be used as an effective therapy to treat prostate cancer bone metastasis in models where the growth of androgen-independent PC-3 and C4-2 tumors in the bone has occurred.
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PMID:Human prostate cancer progression models and therapeutic intervention. 943 28

Malignant human gliomas are the most common forms of primary tumors in the central nerve system. Due to their location and invasive nature, treatment so far has been mainly palliative. Thus, understanding the molecular detail of tumor transformation and progression is crucial for developing effective therapeutic strategy for this fetal tumor. Among the genetic alternations found in these tumors, p53 inactivation and PDGF/PDGFR activation represent the early events, and the loss of chromosome 10 and gene amplification and rearrangement of EGFR represent the late events. Studies with both glioma cell lines and primary tumor tissues have strongly suggested that TGF-alpha and EGFR function as an important autocrine loop in supporting proliferation of human glioma, especially in high grade glioma, since elevated TGF-alpha expression is also found in these high grade tumors. Furthermore, down regulation of the expression of TGF-alpha by antisense constructs has been shown to inhibit several types of human tumor cell growth including glioma. Other means of therapeutic approaches using this autocrine loop as a target also include the use of monoclonal antibodies and their cytotoxic conjugated. Considerable understanding of the EGFR-mediated signal transduction pathways has become available recently, which including GRB2/mSOS1 mediated MAP kinase activation; JAK/STATs pathway; PLC-gamma pathway. However, much work still needs to be done before a specific component of these pathways can be applied for effective control of tumor growth in the clinic.
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PMID:The autocrine loop of TGF-alpha/EGFR and brain tumors. 944 27

The effect of the antiviral agent (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine (cidofovir) on the EBV-associated tumor nasopharyngeal carcinoma (NPC) was evaluated in NPC xenografts in athymic mice. Intratumoral injection arrested tumor growth within 1 week, and by 4 weeks, tumors regressed to 8-75% (39 +/- 33%) of the original size, whereas control tumors injected with PBS grew to 282 +/- 25% of the original size. Ganciclovir slowed but did not arrest or cause regression of tumor growth. A striking antitumor effect was also produced by systemic administration; at 4 weeks, tumors were 79 +/- 49% of the original size, compared with 635 +/- 91% for the controls. Widespread apoptosis was detected after treatment for 2-6 days in C15 as well as two other NPC xenografts, C17 and C18; the latter NPCs have mutations in the p53 gene. These data indicate that cidofovir induces rapid cell death through apoptosis in EBV-transformed epithelial cells.
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PMID:The antiviral agent cidofovir [(S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine] has pronounced activity against nasopharyngeal carcinoma grown in nude mice. 945 76

We demonstrate that targeted expression of SV40 large T antigen (TAg) to the urethral (periurethral) and bulbourethral gland epithelium leads to adenocarcinoma formation in these tissues after 7 months of age, which are extremely rare sites for spontaneous tumor formation in humans. The development of proliferative lesions in the urethral gland predictably follows a temporal course of progression with approximately one third of male animals developing urethral tumors by 1 year of age. Tumor progression in these organs correlates to the level of TAg and p53 expression. Immunoprecipitation confirmed that SV40 TAg protein was bound to p53 and Rb p110 in vivo. Expression of transforming growth factor beta (TGFbetas) was evaluated during tumor progression of urethral gland carcinomas. Elevations of intracellular and extracellular TGFbeta1 and extracellular TGFbeta3 were found in preneoplastic and neoplastic lesions, suggesting that increased TGFbetas may augment tumor growth. c-Met expression showed a tendency for increased expression in the urethral gland carcinomas. We speculate that the directed expression of SV40 TAg by the hormone responsive C3(1) gene and subsequent tumor formation in these organs is influenced by androgens, since these tissues and carcinomas express androgen receptor (AR) and arise only in male transgenic mice. Several cell lines established from the urethral carcinomas were also shown to express AR, but are not androgen dependent in culture. To our knowledge, this is the first transgenic animal model for urethral and bulbourethral carcinomas. This transgenic mouse model and the cell lines derived from it may provide a unique opportunity for dissecting molecular mechanisms involved in the tumorigenesis of these organs which otherwise rarely develop cancer.
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PMID:Altered expression of transforming growth factor betas during urethral and bulbourethral gland tumor progression in transgenic mice carrying the androgen-responsive C3(1) 5' flanking region fused to SV40 large T antigen. 947 12

In tumors, resistance to chemotherapeutic drugs that alkylate the O6 position of guanine correlates with the levels of the DNA repair protein, O6-alkylguanine DNA alkyltransferase (AGT). The expression of AGT gene in human breast tumors was evaluated at the level of the single cell, to better understand the distribution of alkylation resistant cells within the tumor. Compared to normal breast ductal cells, the level of AGT expression in the breast tumor cells increased 2-fold. There was no significant association between AGT expression and tumor grade and metastatic malignancy. The up-regulation of AGT was not directly linked to the expression of cyclins D1 and D3, estrogen receptor, p53 and c-erbB-2, genes involved in cell cycle regulation and tumor growth. The elevated expression of AGT in human breast ductal carcinoma cells appeared to be a general characteristic of breast tumors, and suggests that prior treatment with analogs of O6-alkylguanine that inactivate AGT protein, should render the AGT expressing tumor cells sensitive to drugs that alkylate O6-guanine.
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PMID:Expression of the O6-alkylguanine-DNA alkyltransferase gene is elevated in human breast tumor cells. 949 26

The tumor-derived antigen 90K (Mac-2 BP) is a widely expressed, secreted glycoprotein found in the serum of healthy individuals and at elevated levels in the serum of patients with breast cancer and other types of cancer. The precise function of 90K, particularly in the context of tumor-host relationships, has not yet been established. In this study, the clinical significance of 90K mRNA expression was studied in relation to other established prognostic parameters in 86 patients with primary breast carcinoma. The 2.2-kb 90K message was detected in all tumor samples, but there was marked variation in expression levels from tumor to tumor. Patients were classified into 2 groups on the basis of 90K expression: group 1 (n = 62) included patients with low expression, and group 2 (n = 24) consisted of patients with high expression. An inverse significant correlation was found between the levels of 90K mRNA expression and overexpression of c-erbB2/Neu receptor kinase, a marker of poor prognosis for patients with breast cancer. There was no significant difference between the groups with respect to tumor size, number of involved axillary lymph nodes, hormone-receptor status, p53 expression or proliferation activity as estimated by Ki-67 count. Similarly, no association was found between the level of 90K expression and the risk of death from breast cancer. These data are at variance with published findings showing that high serum 90K levels are associated with poor survival. Significantly, investigation of 90K-gene expression in peripheral-blood mononuclear cells (PBMC) revealed higher levels of 90K message in PBMC of breast-cancer patients than in healthy individuals. This new finding suggests that PBMC activated in response to tumor growth and progression may be an important source of serum 90K in breast cancer.
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PMID:90K (MAC-2 BP) gene expression in breast cancer and evidence for the production of 90K by peripheral-blood mononuclear cells. 949 53


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