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

Gastric cancer is one of the leading causes of cancer mortality in the world. Gastric adenocarcinomas account for more than 95% of gastric tumors, whereas gastrointestinal stromal tumors (GISTs) are the most common neoplasms of the rare gastric mesenchymal tumors. Although the incidence of mid-distal gastric adenocarcinomas is decreasing, the incidence of gastroesophageal junctional tumors and Barrett's adenocarcinomas is increasing for unknown reasons. The majority of gastric tumors are sporadic in nature. However, there are rare, inherited gastric cancer predisposition traits, such as germline p53 (Li-Fraumeni syndrome) as well as E-cadherin (CDH1) alterations in familial diffuse gastric cancers. Gastric cancer has been observed to be part of the spectrum of neoplasms associated with germline mismatch repair gene (MMR) alterations that give rise to the hereditary nonpolyposis colorectal cancer (HNPCC) entity. Comparative genomic hybridization analyses have identified several amplifications and losses of DNA copy numbers in gastric cancers. Loss of heterozygosity (LOH) studies have shown several chromosomal loci with significant allelic loss, thus indicating the possibility of harboring a tumor suppressor gene important in gastric tumorigenesis. Microsatellite instability (MIS) and associated alteration of the TGF-bIIR, IGFRII, BAX, E2F-4, hMSH3, and hMSH6 genes are found in a subset of gastric carcinomas. Cell adhesion molecule abnormalities such as those involving CDH1 may play an important role in diffuse-type gastric cancer development. Although, multiple somatic alterations have been described in gastric carcinomas at the molecular level, the significance of these changes in gastric tumorigenesis remains to be established in most instances. The critical molecular alterations in gastric cancers that may lead to advances in our armamentarium to combat this lethal disease remain to be fully characterized.
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PMID:Molecular biology of gastric cancer. 1197 14

Inflammatory fibroid polyps (IFPs) are rare mesenchymal tumors of the gastrointestinal tract that consist of spindle-shaped stromal cells and an inflammatory infiltrate rich in eosinophils. Their etiology and histogenesis remain unknown. Based on previous reports of their immunoreactivity for CD34 and c-kit biomarkers, IFPs have been thought to be related to gastrointestinal stromal tumors (GISTs). After reviewing the current literature and examining IFPs at the light microscopic level, we evaluated a series of IFPs using an extensive panel of immunohistochemical and in situ hybridization markers in an effort to gain insight into their etiology and histogenesis and to determine their true relationship to GISTs. Sixteen routinely processed IFP specimens (14 gastric, 1 ileal, and 1 rectal) were immunohistochemically stained for antibodies to CD34, HMB-45, desmin, smooth muscle actin, calponin, h-caldesmon, anaplastic lymphoma kinase, S-100 protein, epithelial membrane antigen, c-kit (CD117), stem cell factor (SCF/N19 or kit ligand), p53, bcl-2, cyclin D1, and human herpesvirus-8 (HHV8). In situ hybridization for Epstein-Barr virus-encoded RNA (EBER) was also performed. Ten cases were further evaluated for the dendritic cell markers fascin, CD21, CD23, and CD35. Stromal cells were diffusely positive for CD34 and fascin in all (100%) cases, and these stromal cells were, in addition, immunoreactive for calponin and smooth muscle actin in 88% and 25% of cases, respectively. CD35 was also found to be focally reactive in the stromal cells. Cyclin-D1 was overexpressed in all (100%) IFPs. All other immunohistochemical markers and EBER were negative in the stromal cells. These findings suggest that the proliferating stromal cells in IFPs are of dendritic cell origin, with some cases also exhibiting myofibroblastic features. Absence of c-kit, SCF, and h-caldesmon immunoreactivity fails to support a relationship to GISTs. We also conclude that Epstein Barr virus and HHV8 are unlikely etiologic agents of IFPs. Overexpression of cyclin D1 in all cases suggests that a defect in cell-cycle regulation may be involved in the growth of IFPs.
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PMID:Inflammatory fibroid polyps of the gastrointestinal tract: evidence for a dendritic cell origin. 1470 72

A case for primary gastrointestinal stromal tumor (GIST) is described with reference to its ultrastructural characteristics and mutation within the exon 11 of c-kit gene. A forty-seven years old woman complaining of dysphasia was examined by endoscopy, which depicted a submucosal tumor (70 mm in diameter) with ulcerations at the fundus of the stomach. Histopathologically, the tumor cells had large nuclei and eosinophilic cytoplasm and were frequently during mitosis phase. The tumor cells were immunopositive for KIT, CD 34 and vimentin, suggesting their fibroblast-like characteristics. In contrast, desmin and S-100, a smooth muscle and an enteroglial marker, were not immunopositive within the cells. At least 30 % of the tumor cells possessed MIB-I and 20 % of them possessed p53, which are compatible with fast development of the tumor. By electron microscopy, the tumor cells possessed large oval nuclei, abundant mitochondria, caveolae and smooth endoplasmic reticulums, while no gap junctions were seen on the cells: The tumor cells thus possessed interstitial cells-like characteristics at least in part. DNA mutation search for the tumor cells however realized no gain-of-function mutation within the exon 11 of the c-kit gene, suggesting existence of other mechanism for neoplasmic growth of the tumor cells classified as gastrointestinal stromal tumors.
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PMID:A case for gastrointestinal stromal tumor (GIST) with reference to its ultrastructure and 'gain-of-function' mutation. 1471 34

Granulosa cell tumors of the ovary occasionally show admixed Sertoli components, just as tumors that are predominantly Sertoli or Sertoli-Leydig cell tumors can contain minor granulosa elements. Although the immunoprofiles of pure granulosa cell tumors and pure Sertoli cell tumors have been characterized, little is known regarding what immunophenotypic relationships exist between the granulosa and Sertoli components in ovarian sex cord-stromal tumors that contain both elements. Furthermore, it is not completely understood why sex cord-stromal tumors of the ovary with female-type (granulosa) differentiation can produce male-type (Sertoli) differentiation. To better understand why simultaneous differentiation into female-type and male-type components occurs, eight tumors with mixed differentiation were stained with a panel of antibodies to androgen receptor (AR), calretinin, CD10, CD99, estrogen receptor, inhibin, Ki-67, low molecular weight cytokeratin, pancytokeratin, progesterone receptor, p53, and vimentin. Immunohistochemical composite scores were determined separately for the matched pairs of granulosa and Sertoli components in each case. Differences between both components were statistically analyzed using the Wilcoxon signed rank test. AR and vimentin expression showed a difference at the 10% statistical significance level (p < 0.1), demonstrating higher levels of expression in the granulosa components. The differences between the granulosa and Sertoli components in expression of CD99, inhibin, or pancytokeratin were not statistically significant (p > 0.1, each). Statistical calculations could not be made for calretinin, CD10, estrogen receptor, Ki-67, low molecular weight cytokeratin, progesterone receptor, or p53, although the overall mean levels of expression of CD10 and low molecular weight cytokeratin were substantially higher in the Sertoli components. Not surprisingly, the granulosa and Sertoli components of ovarian sex cord-stromal tumors with mixed differentiation show overlapping immunophenotypic profiles consistent with derivation from a common lineage rather than reflecting a composite tumor. However, because components of a sex cord-stromal tumor simultaneously differentiate along granulosa or Sertoli lines, they seem to show preferential expression of certain antigens. CD10 and low molecular weight cytokeratin are more often associated with Sertoli cell differentiation, whereas AR and vimentin expression seem to reflect granulosa differentiation.
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PMID:Comparative immunohistochemical analysis of granulosa and sertoli components in ovarian sex cord-stromal tumors with mixed differentiation: potential implications for derivation of sertoli differentiation in ovarian tumors. 1508 44

In quantitative reverse transcription-polymerase chain reaction (qRT-PCR), normalization using reference genes is a common useful approach, but the validation of suitable reference genes remains a crucial problem. Use of unconfirmed reference genes may lead to misinterpretation of the expression of target genes. The aim of this study was to adapt an adequate statistical approach to identify and validate reference genes suitable for normalization in qRT-PCR assays. We introduce the equivalence test for the identification of stably expressed reference genes. To evaluate the advantages of this test, the expression of five genes widely used as reference genes (18S, B2M, HPRT1, LMNB1, and SDHA), and of two target genes (TP53 and MMP2), was determined with qRT-PCR in different tissues (clear cell renal cell carcinoma, colon carcinoma, and gastrointestinal stromal tumors). We demonstrate that a stable expression of a reference gene in one tumor type does not predict a stable expression in another tumor type. In addition, we found that even within one tumor type, the expression of a reference gene was not stable for different biological groupwise comparisons. These observations confirm that there is no universal reference gene and underline the importance of specific validation of potential reference genes for any experimental condition.
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PMID:Equivalence test in quantitative reverse transcription polymerase chain reaction: confirmation of reference genes suitable for normalization. 1551 65

ONYX-015 is a provisionally replication competent adenovirus with oncolytic activity in cells with malfunctioning p53. Sarcomas represent a rational target for this approach given the high frequency of p53 mutations (40-75%) and MDM-2 amplification (10-30%). We, therefore, undertook a phase I/II study of ONYX-015, days 1-5 every month administered intratumorally under radiographic guidance, in combination with MAP (mitomycin-C, doxorubicin, cisplatin) chemotherapy in patients with advanced sarcoma. Six patients were treated. Injected lesions included liver metastases in four patients and chest wall metastases in two patients. Sarcoma histologies were gastrointestinal stromal tumors (GIST, two patients), leiomyosarcoma (two patients), liposarcoma (one patient), and malignant peripheral nerve sheath tumor (1 patient). Dose escalation was performed from 10(9) plaque forming units (PFU)/dose (total dose of 5 x 10(9) PFU/cycle) to 10(10) PFU/dose (total dose of 5 x 10(10) PFU/cycle) without dose-limiting toxicity being encountered. Immunohistochemistry of the metastatic lesions prior to treatment showed that five out of six patients were positive for p53, while two patients also had mdm-2 overexpression. Adenoviral replication was detected in two out of six patient biopsies on day 5 of the first cycle, by in situ hybridization (ISH). Both patients were treated at the highest dose level. ONYX-015 viral DNA was detected by quantitative PCR in the plasma of 5/6 patients on day 5 of the first cycle, and up to day 12 (7 days after the last viral dose) in one patient who had extended sampling for viral kinetics performed, suggesting viral replication in sarcoma tissue. One patient with p53 mutation and MDM-2 amplification achieved a partial response to treatment that lasted 11 months. In conclusion, intratumoral administration of ONYX-015 in combination with MAP chemotherapy is well tolerated with no significant toxicity due to ONYX-015 being encountered. Detection of viral DNA in post treatment tumor specimens by ISH and detection of the ONYX-015 genome in the peripheral blood by quantitative PCR, up to 7 days after the last viral dose provide evidence for adenoviral replication. There was evidence of antitumor activity in one out of six patients. Further investigation of this approach in patients with recurrent sarcomas is warranted.
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PMID:Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas. 1564 67

An international meeting on 'New Drugs in Cancer Therapy' was held at the National Tumor Institute of Naples, on 17-18 June 2004. The first session of the meeting focused on analogs of conventional anti-cancer drugs, such as taxanes, platinum compounds, anthracyclines and topoisomerase I inhibitors. The data of a phase II trial of BMS-247550, an epothilone B analog, in patients with renal cell carcinoma were reported. Data were also presented on BBR-3464, a trinucleate platinum analog which was developed on the grounds of greater potency, a more rapid rate of DNA binding and the ability to induce apoptosis regardless of the p53 status of the cell. Pegylated-coated liposomal formulation doxorubicin (Caelyx) has shown efficacy in metastatic breast cancer and in advanced ovarian cancer; sabarubicin is a third-generation anthracycline with equal or superior potency to doxorubicin or idarubicin in a variety of human tumor cell lines of different histotypes. The main mechanisms of resistance to topoisomerase I inhibitors were discussed; data on diflomotecan were reported, showing a narrow therapeutic index of the drug. The second session of the meeting focused on the ErbB family as a target for anti-cancer therapy. Recent evidence of a correlation between epidermal growth factor receptor (EGFR) mutations at exons 18-21 and clinical response of advanced non-small cell lung cancer to gefitinib therapy was commented on. The issue of the association between ErbB2 expression and gefitinib activity was addressed, while clinical data of a phase II study of gefitinib in advanced breast cancer were presented. Monoclonal antibodies targeting EGFR represent another worthwhile way to interfere with EGFR-driven signal transduction. Cetuximab is reaching market registration in advanced colorectal cancer; in particular, due to the results of the BOND study. The recently presented results of the Bonner study strongly support the activity of this drug in head and neck cancer. A step forward in the research on anti-EGFR monoclonal antibodies may be represented by humanized monoclonal antibodies, such as EMD 72000 and ABX-EGF. Imatinib mesylate is probably the most outstanding example of an effective targeted therapy--its activity in gastrointestinal stromal tumors was so exciting that the drug reached the market without undergoing phase III evaluation. The third session of the meeting was on angiogenesis inhibitors. Drugs may interfere with the angiogenic process via different mechanisms and there is a sound rationale for combining anti-angiogenic agents with chemotherapy or multiple anti-angiogenic strategies. Clinical results obtained with direct anti-angiogenic agents have been negative up to now, but some exciting results have been seen with bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF). A few VEGF-tyrosine kinase inhibiting small molecules, such as ZD6474, AZD2171 and PTK/ZK, are undergoing clinical trials. The fourth session of the meeting was on interference with intracellular signal transduction. Farnesyl transferase inhibitors exert their action by interfering with either pro-Ras or RhoB farnesylation. Several clinical studies of different phases with compounds belonging to this class have been carried out, either alone or in combination with chemotherapy; unfortunately, all of them have turned out to be negative. Cell cycle inhibitors, such as CYC-202 and BMS-387032, represent a class of interesting compounds which are in the early phase of development and whose clinical results are eagerly awaited. Another strategy to achieve cell cycle inhibition is to target heat shock protein 90, a molecular chaperone required for protein folding. Clinical data on depsipeptide, a histone deacetylase (HDAC) inhibitor with activity in T cell lymphoma, were presented. Suberoylanilide hydroxamic acid is another small molecular weight inhibitor of HDAC activity. Phase I/II clinical trials have shown low toxicity and evidence of anti-tumor activity; on the other hand, this compound has potential for synergism with radiotherapy, chemotherapy and biologicals.
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PMID:New drugs in cancer therapy, National Tumor Institute, Naples, 17-18 June 2004. 1565 20

Gastrointestinal stromal tumors (GISTs) have a wide spectrum of biologic behavior ranging from benign to malignant. Risk grading based on tumor size and mitotic counts has been proposed in an effort to predict the adverse outcome of GIST in the literature so far. Recent molecular studies have reported the prognostic values of several parameters, including alteration of cell-cycle regulators. The aim of this study was to elucidate the prognostic values of risk grade and alterations of cell-cycle-related proteins, including Ki-67, cyclin A, cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, cdc2, and cdk2, in addition to the conventional factors. Eighty cases of primary c-kit-positive GISTs were classified into 2 cases of very-low-risk grade, 20 cases of low-risk grade, 25 cases of intermediate-risk grade, and 33 cases of high-risk grade. The risk grade was correlated with the presence of metastases and/or recurrence. A high level of Ki-67 and cyclin A expression was correlated with risk grade (P = .0027 and .0441, respectively). Overexpression of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, was associated with the Ki-67 labeling index (LI) (P = .0007, .0475, and .0040, respectively). According to univariate analysis, tumor grade (high risk), tumor size (> or =5 cm), mitotic counts (> or =5/50 high-power fields), Ki-67 LI (> or =4.92%), cyclin A LI (> or =1.61%), and cdc2 LI (> or =1.25%) were all found to be significantly associated with a shorter period of disease-free survival (P = .0001, .0270, .0004, .0001, .0001, and .0011, respectively). According to multivariate analysis, both high Ki-67 LI and high-risk grade were found to be significantly associated with a shorter period of disease-free survival (P = .0083 and .0246, respectively). In conclusion, our results strongly support the hypothesis that Ki-67 LI and risk grade are useful for predicting the aggressive biologic behavior of GISTs. Furthermore, alteration of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, is also a useful marker for predicting aggressive behavior and play an important role, at least in part, in the cell proliferation of GIST.
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PMID:Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. 1608 54

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract. The prediction of the malignant potential of GISTs is still difficult. Altered cell cycle regulation may underlie the tumorigenesis and/or the progression of human malignancies. Although p53 and Bcl-2 have been extensively investigated in GISTs, little is known about the frequency of expression and possible clinical implications of alterations of other cell cycle regulatory proteins in these neoplasms. We have previously investigated the role of loss of p16(INK4A) by loss of heterozygosity and immunohistochemistry in the progression of GISTs and found that loss of heterozygosity of 9p and loss of p16 expression are confined to malignant GISTs. This has led us to investigate the role of other cell cycle regulatory proteins in these tumors. Twenty-three cases of GIST (9 low malignant potential [LMP], 10 primary malignant, and 4 intra-abdominal recurrences) were examined. All cases were strongly positive for KIT (CD117). Immunohistochemical stains were carried out on tissue microarrays to evaluate the expression of proteins involved in the G(1)-S transition and proteins that regulate apoptosis including Rb, E2F1, cyclin D1, CDK4, CDK6, p27(KIP1), p21(WAF1/CIP1), p53, Mdm2, Bcl-2, and Bax. The positive phenotypes identified were as follows: Rb, 39.1%; E2F1, 69.6%; cyclin D1, 30.4%; CDK4, 100%; CDK6, 30.4%; 39.1%; p27(KIP1), 47.8%; p21(WAF1/CIP1), 39.1%; p53, 43.5%; Mdm2, 17.4%; Bcl-2, 91.3%; and Bax, 100%. Malignant GISTs are more likely to be associated with a positive E2F1 and p53 phenotype and a negative p16 and p27(KIP1) phenotype. It was concluded that aberration of the cell cycle regulators is a frequent finding and may be a contributing factor to the pathogenesis of GISTs. While some alterations are seen in LMP and malignant GISTs and therefore may represent an early event in molecular tumorigenesis of GISTs, other alterations are more common in malignant GISTs than LMP and therefore have potential utility as complementary tools for the prognostication of GISTs.
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PMID:Altered expression of cell cycle regulatory proteins in gastrointestinal stromal tumors: markers with potential prognostic implications. 1673 3

With the rapid development of high-throughput techniques for identifying novel specific molecular targets in human cancer over the past few years, attention to targeted cancer therapy has dramatically increased. The term "targeted cancer therapy" refers to a new generation of drugs designed to interfere with a specific molecular target that is believed to play a critical role in tumor growth or progression, is not expressed significantly in normal cells, and is correlated with clinical outcome. There has been a rapid increase in the identification of targets that have potential therapeutic application. The clinical success of the small-molecule kinase inhibitor imatinib mesylate in chronic myeloid leukemia and gastrointestinal stromal tumors has accelerated the development of a new era of molecular targeted cancer therapy. The number of agents under preclinical and clinical investigation has grown accordingly. This emphasis on molecular biology and genetics has also resulted in significant changes in the treatment of gynecologic cancers. Several promising drugs targeting tyrosine kinases (EGFR and Her-2/Neu), mTOR, Raf kinase, proteasome, and histone deacetylases, as well as drugs affecting apoptosis and mitosis, are under development for clinical application. However, some clinical trials of p53 gene therapies and farnesyl transferase inhibitors have had limited success. In this review, we will focus on potential novel targets in gynecologic cancer and the development of targeted therapy and its clinical applications in gynecologic cancer.
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PMID:Targeted therapies in gynecologic cancers. 1684 24


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