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)

Derivatives of camptothecin, an inhibitor of human TOP1, are increasingly being used in treatment of cancers, including leukemia. Sequential combination therapy with inhibitors of TOP2 holds potential promise. Binding of p53 has been shown to inhibit transcription of TOP2 alpha. Down-regulation of TOP2 alpha gene expression by the camptothecin induced DNA damage response may adversely affect the effectiveness of sequential therapy. To address this question, two leukemia cell lines, ML-1 (with wild type p53) and HL-60 (p53 null) were treated with camptothecin to induce similar degree of apoptosis and residual survival. Western blot analysis indicated rapid induction of p53 in ML-1 followed by significant decrease of TOP2 alpha mRNA and protein levels. The expression level of TOP2 alpha in HL60 did not decrease after camptothecin treatment. These results demonstrated that induction of p53 by camptothecin treatment can lead to a decreased level of TOP2 alpha and should be considered in design of combination therapy.
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PMID:Differential effect of camptothecin treatment on topoisomerase II alpha expression in ML-1 and HL-60 leukemia cell lines. 1120 46

Prediction of biologic behavior in adrenocortical neoplasms is difficult because of the lack of availability of reliable clinical, biochemical, and pathologic prognostic markers. Reliable objective markers predictive of clinical outcome in adrenocortical neoplasms are needed to assign optimal treatment of potentially malignant tumors. In the current article, the authors evaluated a set of molecular markers (topoisomerase II alpha (Topo II alpha), MIB-1, p53, human epithelial cadherin (E-cadherin), retinoblastoma gene protein product, and HER-2/neu) and correlated their expression with histologic diagnosis and clinical outcome. Paraffin-embedded, formalin-fixed tissue blocks from 30 cases of adrenocortical neoplasms (15 benign and 15 malignant) were obtained from the surgical pathology archives at the University of Utah Health Sciences Center (Salt Lake City, UT) and the Medical College of Wisconsin (Milwaukee, WI). Age, gender, recurrence, tumor size and weight, hemorrhage, necrosis, pleomorphism, mitotic count, capsular and lymphovascular invasion, hyaline globules, intranuclear inclusions, and immunohistochemical expression of Topo II alpha, p53, MIB-1, E-cadherin, retinoblastoma gene protein product, and HER-2/neu were studied. Clinical data were obtained from the clinical charts, or communication with the treating physician, or both. Adrenocortical neoplasms with hemorrhage, necrosis, large size (>5 cm), weight more than 100 g, nuclear pleomorphism, lymphovascular invasion, and brisk mitotic rate (more than 5 per 30 high-power fields) were more likely to behave in a malignant fashion (P approximately 0.001-0.009). The difference in proliferation indices in benign and malignant neoplasms was statistically significant (P < 0.001). The difference in p53 staining in benign and malignant neoplasms also was statistically significant (P < 0.001). Higher p53 labeling index (>20%) was present in 73% (11/15) of malignant lesions but was found in only 1 of 15 (6.6%) benign lesions. The difference in retinoblastoma staining between benign and malignant neoplasms was statistically significant (P = 0.004). There was no significant difference in staining pattern of E-cadherin expression between benign and malignant lesions. HER-2/neu overexpression was not observed in any of the benign or malignant adrenocortical neoplasms.
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PMID:Value of topoisomerase II alpha, MIB-1, p53, E-cadherin, retinoblastoma gene protein product, and HER-2/neu immunohistochemical expression for the prediction of biologic behavior in adrenocortical neoplasms. 1155 48

Gastric cancer is poorly-responsive to widely used antitumour drugs, the efficacy of which is thought to be related to the capacity of triggering apoptosis. This process requires a series of gene products including a functional p53 protein. We tested the effects of two DNA topoisomerase II poisons, etoposide and doxorubicin, on gastric cancer cell lines with different genetic lesions. We characterised MKN74 and MKN28 cells for p53 gene status and for the expression of p53 and p21 proteins, as well as of topoisomerase II alpha and beta isoforms. After drug treatments, the cells were analysed for drug cytotoxicity, colony forming ability, cell cycle distribution and presence of apoptotic features. Our findings demonstrated that both etoposide and doxorubicin have a potent anti-proliferative effect on gastric cancer cells. Cell death kinetics was different in the two cell lines, MKN74 cells being more sensitive than MKN28 to the drugs. MKN74 cells, although harboring a wt p53 gene, were unable to undergo a massive apoptosis following etoposide treatment. The response of this cell line might be related to the topoisomerase II beta isozyme, the expression of which proved to be undetectable.
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PMID:Effects of topoisomerase II inhibitors on gastric cancer cells characterized by different genetic lesions. 1172 58

A multistep model for pancreatic adenocarcinoma has been proposed recently. In this model, well-defined, noninvasive ductal lesions are recognized as precursors of invasive cancer and have been classified under the nomenclature of pancreatic intraepithelial neoplasia, or PanIN. Increasing evidence suggests that PanINs represent true neoplasms of the pancreatic ductal epithelium, accumulating histologic and genetic abnormalities in their progression toward invasive cancer. We have constructed a tissue microarray containing 55 PanIN lesions of all histologic grades in order to perform a multicomponent analysis of the pancreatic adenocarcinoma progression model. The protein products of 14 genes encompassing a variety of functional classes, such as tumor suppressor genes (p53, Smad4/Dpc4), oncogenes (beta-catenin), cell cycle antigens (p16, cyclin D1), proliferation antigens (Ki-67, topoisomerase II alpha), and epithelial apomucins (MUC1, MUC2, MUC5), as well as "novel" genes described as differentially up-regulated in invasive pancreas cancer by global microarray expression analysis (mesothelin, prostate stem cell antigen, fascin, and 14-3-3varsigma), were analyzed by immunohistochemistry on the PanIN tissue microarray. Comparison of the results from the current study with previously published data performed on routine histologic sections of PanINs demonstrates that tissue microarrays are a valid platform for molecular analysis not only of invasive cancers but of precursor lesions as well. In addition, this study demonstrates that molecular abnormalities in PanINs are not random but can usually be stratified into "early" changes (e.g., expression of MUC5 and prostate stem antigen, or loss of p16), "intermediate" changes (e.g., expression of cyclin D1), and "late" changes (e.g., expression of p53, proliferation antigens, MUC1, mesothelin, and 14-3-3varsigma, or loss of Smad4/Dpc4). Understanding the molecular pathogenesis of precursor lesions of invasive pancreatic adenocarcinomas using a high-throughput tissue microarray-based approach is a valuable adjunct to designing rational strategies for early detection of this lethal neoplasm.
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PMID:Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. 1367 54

1-beta-D-Arabinofuranosylcytosine (Ara-C), a DNA-damaging agent, severely inhibits fetal growth and has teratogenicity. Recently, we reported that Ara-C also causes placental growth retardation and increases placental apoptosis. The aim of the present study is to elucidate the mechanisms of placental injury induced by genotoxic stress and involvement of p53, which mediates apoptosis and cell-cycle arrest after DNA damage. We injected Ara-C into pregnant rats on Day 13 of gestation and examined the placentas from 1 to 48 h after the administration. Terminal deoxynucleotidyltransferase-mediated dUTP end-labeling (TUNEL) revealed that the apoptosis of trophoblastic cells in the placental labyrinth zone increased from 3 h after the treatment and peaked at 6 h before returning to control levels at 48 h. An increase in cleaved caspase-3 immunoreactivity was also detected at 6 h. Proliferative activity as measured by immunohistochemistry for topoisomerase II alpha and by mitotic index significantly decreased after the treatment in the labyrinth zone. Immunoreactivity for p53 protein in the placental labyrinth zone was remarkably enhanced and peaked at 3 h after treatment, although no increase in p53 mRNA expression was detected with a reverse transcription- polymerase chain reaction. Regarding p53 target genes, p21, cyclinG1, and fas mRNA levels increased significantly and peaked at around 9 h after the treatment. These results indicate that Ara-C would induce apoptosis and impair cell proliferation in the placental labyrinth zone, and p53 and its transcriptional target genes may play an important role in the pathogenesis of the Ara-C-induced placental toxicity.
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PMID:Involvement of p53 in 1-beta-D-arabinofuranosylcytosine-induced trophoblastic cell apoptosis and impaired proliferation in rat placenta. 1476 21

Salvicine is a diterpenoid quinone derived from a traditional Chinese medication that has been shown to possess potent in vitro and in vivo antitumor effects. This compound, which inhibits the activity of Topoisomerase II, was found to equipotently kill various multidrug-resistant tumor cells and their corresponding parental counterparts in vitro and to inhibit mdr1/P-gp expression in multidrug-resistant K562/A02 cells. To examine the features of tumor resistance to salvicine, we established a salvicine-resistant tumor cell subline of A549 lung adenocarcinoma cells. Compared with parental cells, A549/SAL cells displayed 8.91-fold resistance to salvicine and an average of 6.70-fold resistance to the antimetabolites. A549/SAL cells, however, were not resistant to alkylating agents, platinum compounds and other naturally-derived antineoplastics. RT-PCR analysis showed that the expression of mRNAs from the mdr-1, MRP, PCNA, topoisomerase II alpha and beta, GSTpi, p21 and GADD45 genes was not altered in the salvicine-resistant subline. In contrast, expression of p53 and bax mRNA was significantly lower, and expression of mdm2 mRNA was significantly higher, in A549/SAL cells compared to A549 cells. A549/SAL cells grew more slowly, and in a more scattered pattern, than A549 cells. In addition, the A549/SAL cells showed enhanced ability to migrate and invade in comparison to the parental cells. These results indicate that exposure to salvicine does not induce a tumor multidrug-resistant phenotype.
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PMID:Characterization of salvicine-resistant lung adenocarcinoma A549/SAL cell line. 1514 50

Platinum agents and paclitaxel (taxol) are among the most effective drugs currently available for treatment of ovarian cancer. One of the hurdles with taxol and platinum- based therapy is the clinical development of resistance to these agents. To investigate the mechanism of drug resistance in human ovarian cancer, we developed and characterized 5 cell models for chemoresistance studies of cisplatin, carboplatin and taxol. We report in this study that these human ovarian carcinoma cell model systems include 2 models for cisplatin resistance, 2 models for carboplatin resistance, and 1 model for taxol resistance. The biological and biochemical characteristics of the models showed that (i), the IC50 values of the drugs for all these resistant cell models were 3 times (or more) higher than those for the parental tumor cells. There also exist varying degrees of cross-resistance to several other chemotherapeutic agents in these systems. Moreover, the intracellular drug accumulations in these cells were significantly reduced as compared to those in the parental cells. (ii), The proliferation rates of these resistant cells were markedly decreased. However, there were no obvious changes in cell cycle distribution in these model systems. (iii), Our results for the expression of a few major drug resistance-related genes revealed that the expression of p53, lrp-1 and mrp-1 was decreased, while the expression of pkc, topo I and topo II beta was increased in the resistant tumor cells as compared with the parental cells. In contrast, no significant alterations in gst-pi and topo II alpha expression were found. Interestingly, the levels of mdr-1 expression were elevated in some models, but were reduced in others, thus suggesting that different pathways are involved in the formation of drug resistance in different cell model systems, and that different mechanisms are responsible for the development of different drug resistances in tumor cells. Taken together, our findings indicate that these models may be potentially used to assess the biochemical and genetic mechanisms of drug resistance in human ovarian cancer and to identify new drug resistance-related genes.
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PMID:Development and characterization of five cell models for chemoresistance studies of human ovarian carcinoma. 1525 75

We report a salivary duct carcinoma (SDC) of parotid gland in a 75-year-old male. Initially, it was studied by fine-needle aspiration, which disclosed features of malignancy consistent with a high-grade carcinoma. Histologically, the tumor showed typical features of SDC, predominantly with a solid and apocrine pattern. The aggressive behavior of this tumor was documented by facial palsy and the presence of 12 regional lymph node metastases. Immunohistochemical study showed positivity for cytokeratins (AE1/AE3), cytokeratin 7, GCDFP-15, C-erbB-2, Mib-1, topoisomerase II alpha, p53, and androgen receptors. Diffuse positivity with chromogranin-A, synaptophysin, and Grimelius stains was also observed, suggesting endocrine features. Phosphotungstic acid hematoxylin, antimitochondrial antigen, progesterone and estrogen receptors, cytokeratin 20, and S-100 stains were negative. To our knowledge, this is the first case reported of SDC exhibiting neuroendocrine differentiation.
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PMID:Salivary duct carcinoma with neuroendocrine features: report of a case with cytological and immunohistochemical study. 1534 92

Comprehensive expression analysis using microarrays has identified a number of differentially expressed genes in smoke-exposed bronchial epithelium and non-small cell lung cancers (NSCLCs). To evaluate the prognostic relevance of these proteins in NSCLCs, we used immunohistochemistry to investigate the expression of beta-catenin (CTNNB1), dickkopf, Xenopus, homolog of 3 (DKK3 gene), fibroblast growth factor receptor 3 (FGFR3), fragile histidine triad (FHIT), tumor protein p53 (TP53), mucin1 (MUC1), topoisomerase II alpha (TOP2A), and glutathione S-transferase-Pi (GST) in a cohort of patients (n = 125). We correlated the expression data with clinicopathologic features and clinical outcome. In addition, SNaPshot multiplex assays (Applied Biosystems, Darmstadt, Germany) and restriction fragment length polymorphism analysis were used to screen for activating point mutations at the hot spots of FGFR3 in a cohort of 30 samples of NSCLC. Using Kaplan-Meier analysis, we observed significantly better overall survival in adenocarcinomas compared with squamous cell cancers (P = .049). Loss of FHIT expression showed a strong association with shorter overall survival in both histologic types of NSCLC (squamous cell cancers, P < .001; adenocarcinomas, P = .001). In adenocarcinomas, the cytoplasmic expression of beta-catenin was associated with shorter survival (P = .012); MUC1 expression was associated with worse prognosis in patients with squamous cell cancers (P = .002). The nuclear staining of TP53 (P = .008) and TOP2A (P = .059) was associated with cancers without lymphonodal metastases. A correlation with positive staining of TOP2A (P = .03) and FGFR3 positivity (P = .057) was found in adenocarcinomas of male patients. Positive MUC1 stainings were associated with squamous cell cancers of male patients (P = .03). DKK3 expression did not show any significant association with clinical outcome or pathologic features. The screening of the FGFR3 sequence in lung cancers showed only wild-type sequences and did not detect mutations in the known hot spots for FGFR3 mutations. We conclude that the immunohistochemical loss of FHIT expression and the positivity for beta-catenin and MUC1 in NSCLC are useful prognostic markers, whereas the variable expression of TP53, TOP2A, and FGFR3 in relation to the different histologic types of NSCLC and sex of the patients is suggestive for different underlying molecular pathways.
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PMID:Prognostic value of FHIT, CTNNB1, and MUC1 expression in non-small cell lung cancer. 1794 85

We evaluated the expression of molecular markers in colorectal adenocarcinoma in relation to p53 protein expression. Tissue samples of 54 patients with colorectal adenocarcinoma were obtained at surgery at university hospitals in the years 2000-2003. These were analyzed by immunohistochemical techniques using primary antibodies for p53, Bcl-2, P-gp, topoisomerase II alpha and Thymidylate Synthase (TS), thymidine phosphorylase/PD- ECGF (TP) and LSAB detection kit. The highest prevalence of expression among six analyzed markers were P-gp and p53 with 77% expression and the lowest one was Topo II with 35% expression. No clinicopathological significance was recorded in colorectal cancer patients. Several immunophenotypes were observed between p53 and other molecular markers. Additionally the prevalence of lack of expression of Bcl-2, Topo II and TS was higher in p53+ tumors than in p53-tumors. A significant association (p = 0.021) existed between p53/Bcl-2 coexpression and mean age of patients (63.5 [10.1]y vs. 52.3 [15.2] y) and between p53/TP coexpression and sex (66.7% male; (p = 0.022). Overexpression of mutated p53 seen in tumor samples may alter the expression pattern of other molecular markers that are predictors of tumor response to chemotherapy regimens. Age and sex of patients could also affect the p53 related proteins such as Bcl-2 and TP, which can affect therapeutic outcome and disease prognosis. These findings emphasize the importance of tumor immunophenotypes as valuable prognostic or predictive markers in clinical settings.
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PMID:Association between p53 expression and Bcl-2, P-glycoprotein, topoisomerase II alpha, thymidylate synthase and thymidine phosphorylase as potential therapeutic targets in colorectal cancer patients. 1909 Jan 49


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