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)

Improvements in surgery and radiotherapy techniques have led to only a modest increase in the 5-year survival rate for patients with head and neck cancer. This is because the pattern of clinical disease is changing, such that locoregional recurrence now accounts for fewer treatment failures, but more patients develop a second primary cancer or distant metastatic disease. In this study, we have used the p53 phage plaque assay, immunocytochemistry, and mutational analysis to assess the contribution of minimal residual cancer and genetic aberrations in clinically normal upper aerodigestive tract mucosa to treatment failure. Eighteen consecutive patients with oral tumors, with conventional clear margins, have been followed for a minimum of 36 months. Molecular assessment identified tumor-positive surgical margins for 6 of 11 assessable patients and additional tumor-positive lymph nodes for three cases. Disseminated malignant cells were detected in the hematopoietic cell compartment for six cases, and one patient had molecular evidence of field cancerization. Locoregional recurrence developed in five patients with tumors harboring a p53 gene mutation; four of these were associated with tumor-positive surgical margins, and one was associated with molecular evidence of field cancerization. Radiotherapy to the primary site did not prevent development of local recurrence when the residual tumor harbored a p53 gene mutation. Three of six cases with a tumor-positive bone marrow aspirate developed distant metastases. These findings reveal that molecular and immunocytochemical detection of minimal residual cancer and field cancerization can help identify patients who may develop locoregional or distant recurrence and justify further studies to evaluate the contribution of these remaining malignant cells to treatment failure.
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PMID:Detection of minimal residual cancer to investigate why oral tumors recur despite seemingly adequate treatment. 1091 16

ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. We undertook a phase II trial of a combination of intratumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck. There were substantial objective responses, including a high proportion of complete responses. By 6 months, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. The toxic effects that occurred were acceptable. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction.
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PMID:a controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. 1093 16

Locoregionally recurrent head and neck squamous cell carcinoma is a logical target for direct delivery of gene therapy approaches. Because the protein p53 plays a role in cell cycle regulation and in apoptosis, p53 gene transfer was initially tested in head and neck cancer patients by injecting the primary or regional tumor with an adenoviral vector possessing wild-type p53. Adenoviral p53 was demonstrated to be safe and well tolerated; furthermore, activity was observed. Several randomized studies of adenoviral p53 are now under way in patients with head and neck squamous cell carcinoma to determine its role as a surgical adjuvant in untreated disease and in combination with DNA-damaging agents.
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PMID:The current status of gene therapy. 1095 37

Diploid tumour cells regularly continue to progress after the development of aneuploid cell populations in head and neck squamous cell carcinomas. The coexistence of aneuploid clones with their diploid progenitor cells provides a unique opportunity to study the order of appearance of p53 mutation and aneuploidy in the same tumour. Multiparameter flow cytometry was therefore applied to 22 oral squamous cell carcinomas to simultaneously assess cellular DNA content and p53 protein expression on a single-cell basis. Concurrent measurements of cytokeratin expression served to identify tumour cells of epithelial origin. One of 5 diploid and 2 of 17 aneuploid carcinomas were p53-negative. For 15 p53-positive aneuploid tumours, overexpression of p53 protein was identified for the aneuploid clones as well as for coexisting diploid tumour cell populations in 14 cases. On the understanding that coexisting diploid and aneuploid tumour cell populations have a common clonal origin, these results provide evidence that aneuploid tumour clones typically develop from p53-deficient diploid progenitor cells. Loss of wild-type p53 function may therefore contribute to the development of aneuploidy in head and neck cancer.
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PMID:Multiparameter flow cytometry for simultaneous assessment of p53 protein expression and cellular DNA content in oral squamous cell carcinomas: evidence for the development of aneuploid clones from p53-deficient diploid progenitor cells. 1102 95

Mutation or inactivation of p53 is known to be present in approximately 50% of human cancers. We propose here a novel strategy for overcoming this problem in mutant p53-targeting cancer therapies. We examined the restoration of radiation-induced p53-dependent apoptosis by a chemical chaperone (glycerol) in human head and neck cancer cells (SAS cells, showing wild-type p53 phenotype). SAS cells transfected with mutant p53 (SAS/m p53) showed radioresistance compared with SAS cells (SAS/ neo) transfected with neo vector as a control, but became radiosensitive when pre-treated with glycerol before X-ray irradiation. Apoptosis in the SAS/m p53 cells was induced by X-rays with glycerol pre-treatment, but not without glycerol pre-treatment, whereas apoptosis in the SAS/ neo cells was induced in both cases. Gel mobility-shift assays showed that after X-ray irradiation combined with glycerol pre-treatment, mp53 was able to bind to the sequence-specific region upstream of the bax gene regulating apoptosis. These results suggest that glycerol is effective in inducing a conformational change of p53 and restoring normal function to mp53, leading to enhanced radiosensitivity through the induction of apoptosis. This novel tool for enhancement of radiosensitivity in cancer cells bearing mp53 may be useful for p53-targeted radiotherapy.
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PMID:Glycerol restores p53-dependent radiosensitivity of human head and neck cancer cells bearing mutant p53. 1110 74

Second primary carcinoma is a peculiar feature of head and neck cancer and represents a form of treatment failure distinct from the recurrence of the primary tumor. Whether altered p53 expression in tumor-distant epithelia at the time of diagnosis is of clinical value as a biomarker for second primary carcinoma development has not been rigorously answered because of the lack of long-term follow-up studies involving a sufficiently large patient cohort. In this prospective study, we have investigated p53 expression in tumor-distant epithelia and in the corresponding primary tumors of 105 head and neck cancer patients by immunohistochemistry on frozen sections. After a median follow-up of 55 months, the clinical course of disease parameters, i.e., local recurrences, lymph node and distant metastasis, incidence of second primary carcinoma, and survival, was evaluated. Overexpression of p53 in tumor-distant epithelia was found in 49 patients (46.7%), and it was independent of the p53 protein status of the primary tumor and of the tumor site, size, stage, and grading. Mucosal p53 overexpression was not associated with local primary recurrences, lymph node or distant metastases, or overall survival. Importantly, mucosal p53 overexpression, but not overexpression in the primary tumors, was significantly associated with an increased incidence of second primary carcinomas (P = 0.0001; Fisher's exact test). When the times to second primary tumor occurrence were analyzed by the Kaplan-Meier method, the difference remained significant (P = 0.005; log rank test). We conclude that IHC staining for p53 overexpression in tumor-distant epithelia provides a simple and rapid tool to identify head and neck cancer patients at increased risk of developing second primary tumors. Because p53 overexpression in these epithelia in our patient cohort was specifically associated with second primary cancer but not with recurrences, at least a fraction of the second primary cancers appears to have resulted from genetic events in the mucosa ("field cancerization").
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PMID:Overexpression of p53 in tumor-distant epithelia of head and neck cancer patients is associated with an increased incidence of second primary carcinoma. 1123 82

The current delineation of the molecular basis of cancer provides a strong rationale to consider gene therapy approaches for cancer as a complement to other cancer therapies. Phase III trials focused on adenoviral vector-mediated delivery of wild-type p53 to compliment p53 mutations were recently initiated for head and neck cancer and ovarian cancer. Clinical testing of the tumor inhibitory gene E1A, delivered by synthetic vectors is ongoing. Positive clinical data from these clinical studies will establish the use of gene therapy as a component of the multimodal treatment for certain cancers.
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PMID:Gene therapy: a molecular approach to cancer treatment. 1124 73

Head and neck squamous cell carcinoma affects more than 500,000 people worldwide each year. Despite optimal treatment with surgery, irradiation, and chemotherapy, disease recurrence and progression remains a common and challenging oncological problem. Recently, interest has developed in identifying novel molecular markers that allow identification of those patients at increased risk for locoregional recurrence and death. This article reviews several such molecular markers studied in head and neck cancer, including p53, angiogenesis-related markers, cyclin D1, and epidermal growth factor receptor. The biological function of these markers and the potential clinical implications are discussed. The purpose of this review is to update the otolaryngologist on a rapidly emerging segment of applied translational research in our field.
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PMID:Molecular markers in head and neck squamous cell carcinoma: their biological function and prognostic significance. 1126 65

The observation that p53 alterations are early events in the tumorigenesis of head and neck cancer and the association with cigarette smoking have prompted us to search for p53 overexpression in the oral mucosa of heavy smokers who have no overt precancerous or cancerous lesions. Formalin-fixed paraffin embedded tissue sections, obtained from oral mucosa of 30 otherwise healthy heavy smokers, were evaluated for tobacco related changes, and immunostained with a mouse monoclonal antibody p53-DO7 for p53 immunoreactivity. Histopathological evaluation revealed hyperplastic changes in twenty eight samples (93%), eight of which also demonstrated dysplastic changes. Positive immunoreaction for p53 was detected in six (20%) of the tissue samples. The study provided significant information about the frequency of hyperplasia, dysplasia, and p53 overexpression in individuals who were heavy smokers. It is suggested, also, that chemoprevention might have some impact in this particular group of individuals.
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PMID:P53 overexpression in normal oral mucosa of heavy smokers. 1127 33

The INK4a gene locus on chromosome 9p21 encodes two proteins, p16(INK4a) and p14(ARF), which influence cell cycle control regulated by pRb and p53. The objective of this study was to use different methods for the analysis of the incidence of changes at the INK4a locus in head and neck cancer (HNSCC). Primary tumours were analysed for allelic imbalances (AI) with microsatellite markers for chromosome 9, by immunohistochemistry (IHC) and IHC with enhanced sensitivity by tyramide signal amplification (TSA-IHC), and by RT-PCR. No homozygous deletions at 9p21 were detected. AI at 9p21, which was found in approximately 60% of the tumours, completely failed to indicate the functional inactivation of the two INK4a gene products. Immunostaining of normal squamous epithelia revealed very low levels of p16(INK4a), whereas p14(ARF) was readily detectable. In 160 tumours, IHC suggested a loss of p16(INK4a) expression in 90%. However, by TSA-IHC, only 53.7% showed loss of p16(INK4a) expression, and this was consistent with the RT-PCR analyses. In 100 tumours analysed for both proteins, selective loss of p16(INK4a) occurred in 37%; loss of p14(ARF) was found in only 15%, and selective loss in only 4%; 11% of the tumours had lost both proteins. We conclude that only IHC with high sensitivity and the combined expression analysis of mRNAs and proteins is suitable for studying the role of INK4a in HNSCC. The INK4a gene expression defects are frequent but not universal and primarily affect p16(INK4a). Their clinical impact is still not clear.
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PMID:Detailed gene expression analysis but not microsatellite marker analysis of 9p21 reveals differential defects in the INK4a gene locus in the majority of head and neck cancers. 1143 63


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