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)

of ZD1839 ("Iressa") is an orally active, selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), which blocks signal transduction pathways implicated in proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. Permanent downstream activation of the mitogen-activated protein kinase pathway can theoretically bypass the upstream block of epidermal growth factor receptor-dependent mitogen-activated protein kinase activation at the epidermal growth factor receptor level. We investigated the impact of epidermal growth factor receptor content, p53 status and mitogen-activated protein kinase signalling status on ZD1839 sensitivity in a panel of human tumour cell lines: seven head and neck cancer cell lines and two colon cancer cell lines (LoVo, HT29) with derivatives differing only by a specific modification in p53 status (LoVo p53 wt + p53 mut cells, HT29 p53 mut + p53 wt rescued cells). The antiproliferative activity of ZD1839 was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test. ZD1839 concentrations ranged from 0.2-200 microM (48 h exposure). Epidermal growth factor receptor expression, p53 status and p42/p44 (for testing a constitutively active mitogen-activated protein kinase pathway status) were determined by competition analysis (Scatchard plots), denaturing gradient cell electrophoresis and Western blot, respectively. Epidermal growth factor receptor levels ranged from 388 to 33794 fmol mg(-1) protein, a range that is similar to that found in head and neck tumours. The IC(50) values for cell sensitivity to ZD1839 ranged from 6 to 31 microM and a significant inverse correlation (P=0.022, r=0.82) between IC(50) values and epidermal growth factor receptor levels was observed. There was no influence of p53 status on the sensitivity to ZD1839. In two head and neck cancer cell lines with comparably elevated epidermal growth factor receptor expression, a two-fold higher ZD1839 IC(50) value was found for the one with a constitutively active mitogen-activated protein kinase. In conclusion, ZD1839 was active against cells with a range of epidermal growth factor receptor levels, although more so in cells with higher epidermal growth factor receptor expression. Activity was unaffected by p53 status, but was reduced in cells strongly dependent on epidermal growth factor receptor signalling in the presence of an intrinsically activated mitogen-activated protein kinase pathway.
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PMID:Influence of epidermal growth factor receptor (EGFR), p53 and intrinsic MAP kinase pathway status of tumour cells on the antiproliferative effect of ZD1839 ("Iressa"). 1198 89

Prognostication of head and neck cancer (HNCC) involves molecular identification of residual tumor cells, prediction of recurrence, distant metastases or secondary tumors and prediction of the sensitvity to therapy. Biomarkers of HNCC are mutations of p53, p16 and amplification of Cyclin D and E2F4. One hundred and fifty-two HNCC cases have been evaluated for p53, hMLH1, Cyclin D and p16 gene alterations using PCR-SSCP and Western blot analysis. P53 mutations of HNCC have been found in 37.5% of cases. However, 11% of the cases showed p53 mutations in the normal peritumoral mucosa suggesting "field cancerization" process. Mismatch-repair gene mutations (MMR: hMHL1 and hMSH2) occurred with 17 and 8.6% frequency, respectively, while E2F4 mutations were even more frequent (21.4%) in HNCC. Our data suggest that E2F4 overexpression can be caused by the inactivation of the p16 gene in HNCC, while its mutations are most probably associated to the mutations of the MMR genes. These molecular informations can help to predict the biological potential of HNCC as well as the probability of the development of secondary HNCCs.
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PMID:[Genetic marker analysis in head and neck cancer] 1205 Jul 11

It is important to examine the abnormality of the entire p53 tumor suppressor pathway in head and neck cancer. We examined the mRNA expressions of p53 regulatory factors, p33ING1 and p14ARF, and a p53-target gene, p21WAF1 in head and neck cancer. Nine of 14 benign pleomorphic adenomas (PAs) and 7 of 8 malignant salivary gland tumors (MSGTs) expressed p33ING1 mRNA. Thirteen of 14 PAs expressed p14ARF mRNA, however, only 1 of 8 MSGTs expressed p14ARF mRNA. Eight of 14 PAs and 7 of 8 MSGTs expressed p21WAF1 mRNA. In salivary gland tumors, there was clear correlation between the expression of p33ING1 and p21WAF1 (p<0.0001, r2=0.53). However, there was no correlation between the expression of p14ARF and p21WAF1 (p=0.6543, r2=0.009). Twenty-six of 28 oral squamous cell carcinomas (SCCs) expressed p33ING1 mRNA. Nineteen of 28 oral SCCs expressed p14ARF mRNA. All of the oral SCCs expressed p21WAF1 mRNA. In oral SCCs, the expressions of both p33ING1 (p=0.009, r2=0.181) and p14ARF (p=0.0009, r2=0.271) correlated with the expression of p21WAF1. Interestingly, 24 of 26 oral SCCs (92%) showed either abnormality of p53 itself or loss of expression of p53 regulatory factors, p33ING or p14ARF. These results suggest that head and neck cancer often involve the dysfunction of p53 tumor suppressor pathway.
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PMID:Dysfunction of the p53 tumor suppressor pathway in head and neck cancer. 1206 58

The frequent loss or promoter methylation of the tumor suppressor gene p16 in head and neck cancer suggests an etiologic role of p16 in this disease. Two adjacent polymorphisms of p16 exon 3, C540G and C580T, were identified recently. C540G is associated with low expression of p53, and both polymorphisms are associated with tumor aggressiveness, suggesting a possible functional relevance. We hypothesized that these two polymorphisms, particularly their haplotypes, are associated with the risk of developing squamous cell carcinoma of the head and neck (SCCHN). To test this hypothesis, we conducted a hospital-based case-control study of 208 patients with SCCHN and 224 cancer-free control subjects to evaluate the association between p16 genotypes/haplotypes and the risk of SCCHN, using a PCR-single strand conformation polymorphism-based genotyping assay. However, our results suggested that no significant differences exist in the distribution of p16 C540G and C580T genotypes between cases and controls. For the C540G polymorphism, the CC, CG, and GG genotype frequencies were 76.9%, 22.1%, and 1.0%, respectively, in the cases, compared with 76.8%, 21.9%, and 1.3%, respectively, for the controls. For the C580T polymorphism, the CC, CT, and TT genotype frequencies were 83.6%, 15.9%, and 0.5%, respectively, in the cases, compared with 82.6%, 16.5%, and 0.9%, respectively, for the controls. The frequencies of three predominant 540C/580C, 540G/580C, and 540C/580T haplotype alleles were distributed similarly in the cases (79.6%, 12.0%, and 8.4%) and in the controls (78.6%, 12.3%, and 9.1%). None of these differences were statistically significant. We conclude that these polymorphic p16 genotypes or haplotypes may not play a major role in the etiology of SCCHN, if any. However, our limited sample size and power call for larger studies for additional verification of our findings.
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PMID:Haplotypes of two variants in p16 (CDKN2/MTS-1/INK4a) exon 3 and risk of squamous cell carcinoma of the head and neck: a case-control study. 1254 May 8

Polyethylenimine (PEI) derivatives are polycationic nonviral vectors for gene transfer. Previous results achieved in vitro in head and neck cancer cells demonstrated that glucosylated PEI yields higher gene transfer efficiency and longer transgene expression than unsubstituted PEI. Using glucosylated PEI, p53 gene transfer was successfully achieved with subsequent recovery of P53 protein expression and induction of spontaneous apoptosis. The present study reports in vivo data achieved in human head and neck squamous cell carcinoma xenografted mice. Using biotinylated PEI and histochemistry analysis, the vector was found to diffuse in the proliferating cells of the tumor tissue, sparing necrotic areas. No diffusion was observed inside keratinized area composed of nonproliferating, mature differentiated cells. Using green fluorescent protein (GFP) transfection and fluorescence microscopy, the transgene expression was mainly observed at the periphery of the tumor containing proliferating cells. GFP expression appeared lower inside the tumor depth. Quantitative transgene expression kinetics was then determined using luciferase as reporter gene. The maximal transgene expression was achieved 48 hours after intratumoral injection of glucosylated PEI/DNA complexes. The highest gene transfer efficacy was achieved 48 hours after two intratumoral injection. After transfection of wild-type p53, tumor growth inhibition was observed in tumor-bearing mice receiving intratumoral injection of glucosylated PEI/DNA complexes repeated twice weekly. Tumor growth inhibition was maintained under continuous treatment using the same schedule. In all experiments, no noticeable toxicity was observed. The present results demonstrate the feasibility and the tumor growth inhibition potency of nonviral gene transfer using glucosylated polyethylenimine.
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PMID:In vivo growth inhibitory effect of iterative wild-type p53 gene transfer in human head and neck carcinoma xenografts using glucosylated polyethylenimine nonviral vector. 1213 33

Squamous cell carcinoma of the head and neck region (HNSCC) is the sixth most frequent cancer worldwide, comprising almost 50% of all malignancies in some developing nations. In the United States, 30,000 new cases and 8,000 deaths are reported each year. Survival rates vary depending on tobacco and alcohol consumption, age, gender, ethnic background, and geographic area. This variability reflects the multifactorial pathogenesis of the disease. Early detection and diagnosis has increased survival but the overall 5 year rate of 50% is among the lowest of the major cancers. Differences between normal epithelium and cancer cells of the upper aerodigestive tract arise from specific alterations in genes controlling DNA repair, proliferation, immortalization, apoptosis, invasion, and angiogenesis. These proteins include both tumor suppressors and activating oncogenes which regulate a wide variety of intracellular signaling pathways. Included in these pathways are growth factor receptors, signal transducers, and transcription factors which regulate DNA damage response, cell cycle arrest, and programmed cell death. In head and neck cancer, alterations of three signaling pathways occur with sufficient frequency and produce such dramatic phenotypic changes as to be considered the critical transforming events of the disease. These changes include mutation of the p53 tumor suppressor, inactivation of the cyclin dependent kinase inhibitor p16, and overexpression of epidermal growth factor receptor (EGFR). This review will focus on the molecular changes which occur in these pathways and how they contribute to the pathogenesis of HNSCC.
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PMID:Molecular pathology of head and neck cancer. 1216 2

The development of second primary tumors has a negative impact on the prognosis of head and neck squamous cell carcinoma. Previously, we detected genetically altered and tumor-related mucosal lesions in the resection margins in 25% of unselected head and neck squamous cell carcinoma patients (Tabor MP, Brakenhoff RH, van Houten VMM, Kummer JA, Snel MHJ, Snijders PJF, Snow GB, Leemans CR, Braakhuis BJM: Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications. Clin Cancer Res 2001, 7: 1523-1532). The aim of this study was to determine whether first and second primary tumors are clonally related and originate from a single genetically altered field. From 10 patients we analyzed the first tumor of the oral cavity or oropharynx, the >3-cm remote second primary tumor, and the mucosa from the tumor-free margins from both resection specimens. We compared TP53 mutations and loss of heterozygosity profiles using 19 microsatellite markers at chromosomes 3p, 9p, 13q, and 17p. In all patients, genetically altered mucosal lesions were detected in at least one resection margin from both first and second primary tumor. Evidence for a common clonal origin of the first tumor, second primary tumor, and the intervening mucosa was found for at least 6 of 10 patients. Our results indicate that a proportion of multiple primary tumors have developed within a single preneoplastic field. Based on different etiology and clinical consequences, we propose that independent second primary tumors should be distinguished from second field tumors, that arise from the same genetically altered field the first tumor has developed from.
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PMID:Multiple head and neck tumors frequently originate from a single preneoplastic lesion. 1221 34

A number of studies have shown that tamoxifen increases the sensitivity of several types of solid tumours to cisplatin without increasing the associated side effects. The cellular mechanisms responsible for this increased sensitivity are currently unknown. In this study we have investigated whether tamoxifen alone or in combination with cisplatin could induce apoptosis in head and neck squamous cell carcinoma (HNSCC) cell lines. We have shown that tamoxifen treatment resulted in G(1) arrest in two cell lines, HN5 and HN6. Tamoxifen induced growth suppression was independent of p53 status but resulted in up-regulation of cyclin dependent kinase inhibitors (CDKIs) p21/Waf-1, p27/Kip1 and p15/INK4a. Furthermore, tamoxifen treatment resulted in an increased level of hypophosphorylated active RB. Cisplatin induced p53 independent apoptosis in both head and neck cancer cell lines. There was a significant sensitizing effect of tamoxifen on cisplatin-induced apoptosis in HN5 and HN6 cells, with the combined treatment being more effective in inducing apoptosis. Addition of tamoxifen did not result in significant inhibition of PKC activity in HN5 and HN6 cells. However, tamoxifen treatment resulted in increased secretion of TGF-beta1 by HN5 and HN6 cells. An anti-TGF-beta blocking antibody prevented both the blockade of cellular proliferation and the increased expression of CDKIs associated with tamoxifen treatment of HN5 and HN6 cells. These results show that tamoxifen alone induces a transient G(1) arrest that greatly sensitizes the cells to apoptosis induced by cisplatin. We have shown that the mechanism for this p53-independent G(1) arrest and apoptosis is at least partly due to the activation of TGF-beta1 resulting in the induction of p15/INK4b, p27/Kip-1, p21/Waf-1 and RB hypophosphorylation. These in vitro results suggest that combination of tamoxifen and cisplatin might be a more effective treatment for head and neck cancers than single modality therapy.
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PMID:Tamoxifen inhibits the growth of head and neck cancer cells and sensitizes these cells to cisplatin induced-apoptosis: role of TGF-beta1. 1237 63

DNA adducts associated with tobacco smoking could provide a marker of biologically effective dose of tobacco carcinogens and improve individual cancer risk prediction. A significant number of clinical and epidemiologic studies have reported associations of increased DNA adduct levels with the occurrence of the prevalent tobacco related cancers including cancer of the lung, head and neck, and bladder. The inducibility of DNA adducts following in vitro treatments using blood lymphocytes also appears to be a risk factor in the development of lung and head and neck cancer. Corroborative evidence pointing to the importance of DNA adducts in tobacco carcinogenesis include numerous studies showing associations of tobacco smoke exposure with the induction of DNA adducts in humans in vivo. Further effort is necessary, however, to more fully characterize the dose-response relationship between smoking and DNA adducts in exposed target and surrogate tissues. The relationship between gene polymorphisms thought to modify tobacco-related cancer risk and DNA adduct levels is complex. Results of some DNA adduct studies (both in vitro and in vivo) appear inconsistent with the epidemiologic findings. This is evident for polymorphisms involving both carcinogen metabolism (e.g. GSTP1) and DNA repair (e.g. XRCC1). Molecular studies of human tumors suggest associations of p53 mutation with DNA adducts and have revealed correlations of DNA adduct levels with somatic alterations (e.g. 3p21 LOH) that are thought to occur at the very earliest stages of tobacco carcinogenesis. More research is needed to assess the relationship between endogenous sources of DNA adducts and tobacco smoke exposure and the relative oncogenic effects of chemically stable versus unstable DNA adducts. Many potentially fruitful new avenues of cancer research are emerging that integrate DNA adduct analyses with assessments of smoking, genetics, diet and ambient air quality. These investigations aim to understand the multifactorial nature of interindividual variability in response to tobacco carcinogens. As these trends continue a variety of innovative study designs and approaches will become important in human populations.
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PMID:DNA adduct burden and tobacco carcinogenesis. 1237 80

Tobacco-associated carcinogens are catalyzed by microsomal epoxide hydrolase (mEH). Combinations of the Y113H and H139R polymorphic EPHX1 variants have been assumed to alter the enzyme activity and thus the risk of squamous cell head and neck cancer (SCCHN). Based on in vitro data, a putative low, medium and high mEH activity has been associated with combinations of these genotypes, and the respective activity categories have been frequently used in the estimation of risks for smoking-related cancers. We investigated the SCCHN risk for EPHX1 genotypes among 280 cases and 289 controls. We could not detect main effects of the EPHX1 genotypes, but a smaller risk of the 139HR genotype in smokers (odds ratio, OR, 0.57; 95% confidence interval, CI, 0.34-0.95). We could not confirm an increase of the SCCHN risk for genotype combinations according to a putative medium and high enzyme activity (OR 1.28, 95% CI 0.84-1.96; OR 0.98, 95% CI 0.58-1.64, respectively), but a significant heterogeneity of the estimated risks for the singular genotypes within these categories among smokers ( P=0.02). Further, p53 mutations among smoking cases were less frequent in the group with a putative high enzyme activity, although insignificant due to small numbers (OR 0.54, 95% CI 0.13-2.17). This supports uncertainties in categorizing genotypes with respect to limited enzyme activity data, especially when taken from in vitro experiments.
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PMID:Association between head and neck cancer and microsomal epoxide hydrolase genotypes. 1249 Oct 39


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