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)

Twenty four squamous cell carcinomas of the head and neck (HNSCC) of stage II to IV were evaluated for the expression of potential markers such as oncogenes and tumor suppressor genes in drug-resistance behavior. We have analysed the c-myc, c-jun, c-raf and N-ras and p53 expression in total RNA preparation from tumor biopsies obtained before treatment. The patients underwent chemotherapy including 5-fluorouracil and cisplatinum. No significant differences in c-raf and N-ras expression were found in responding or resistant patients. However, resistance to chemotherapy was associated with low expression of c-myc (P < 0.025) or high expression of c-jun (P < 0.001). In addition, p53 mRNA pre-therapeutic level was increased in unresponsive patients to chemotherapy (P < 0.05). Therefore, analysis of the expression of c-myc, c-jun oncogenes and p53 tumor suppressor gene in tumor cells before initiation of therapy may define a subset of patients with potentially better prognosis.
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PMID:[Drug resistance, oncogenes, and anti-oncogenes in epithelial tumors]. 772 55

In order to determine whether or not the p53 gene is involved in the malignant transformation of the head and neck carcinoma HNSCC, we have analyzed archival specimens from 527 primary head and neck lesions and 27 corresponding lymph node metastases. Nuclear p53 protein was present in 107 of 190 (56%) dysplasias, 61 of 102 (60%) carcinoma in situ (CIS), and 262 of 493 (53%) carcinomas. The p53 score did not increase significantly with progression of these lesions from dysplasia to CIS and to carcinoma. All 357 normal samples of head and neck tissues were negative. The majority of the 172 sets of premalignant and malignant lesions displayed concordant p53 staining patterns. The staining was incongruous in only six cases. The p53 staining results were congruent in all 27 pairs of primary and metastatic (lymph nodes) tumors. These data strongly suggest that p53 protein could be altered in a very early phase of the head and neck tumorigenesis and is maintained during tumor progression and metastatic spread. Mutations in p53 were examined in 11 cases that exhibited high levels of p53 protein as detected by immunohistochemistry using PAb 1801 MAb. Mutation analysis was performed by direct sequencing of the PCR amplification products of exons 5 through 8, which contain greater than 90% of p53 mutations found in tumors. Three of 11 HNSCC had mutations at codon 130 (C to A), 193 (A to T), 283 (G to C), respectively. No mutations were found in the other 8 samples within the regions examined. However, they may have mutations in unsequenced regions of p53 or may have wild type protein that accumulates for other reasons.
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PMID:Overexpression of p53 protein is common in premalignant head and neck lesions. 784 May 33

Loss of wild-type p53, either through deletion or mutation, has been demonstrated in most squamous cell carcinomas of the head and neck (HNSCC). Whether these mutant molecules contribute to tumor progression purely through loss of wild-type functions or by growth-promoting mechanisms, however, remains unclear. To begin to address these issues, we isolated a series of p53 cDNAs from HNSCC cell lines that contain missense or nonsense point mutations, insertions, or deletions. The ability of each of these molecules to transform NIH/3T3 cells to a malignant phenotype was assessed by stable transfection and expression under the control of a strong heterologous promoter. NIH/3T3 cells transfected with pLTR6p53, which harbors an H179L missense mutation, formed large tumors rapidly (in less than 4 wk) when transplanted to athymic mice, as did cells expressing pLTR13p53, which had undergone a V173F missense mutation and an in-frame deletion of 48 bp between codons 208 and 223. Cells transfected with pLTR17p53, predicted from the nucleotide sequence to encode a severely truncated p53 corresponding to the N-terminal 56 amino acids, also formed tumors. Cells transfected with pLTR15p53, which was predicted to encode a less severely truncated molecule, formed much smaller tumors and at lower frequencies. NIH/3T3 cells transfected with pLTR12p53 (exon 7 splice donor mutant), pLTRwtp53 (wild-type p53), or vector alone failed to form tumors for up to 2 mo after transplantation. pLTR6p53-transfected cells exhibited a highly malignant phenotype with invasion of regional lymph nodes, mediastinal and lung metastases, invasion of the abdominal wall, and dissemination throughout the peritoneal cavity. Histological assessment of the tumors revealed intensely vascularized fibrosarcomas with numerous cellular atypia, including frequent and aberrant mitoses. Tumor explants were recultured, and northern blot analysis of cellular RNA confirmed that the expression of exogenous p53 was maintained in each case. These data indicate that different p53 mutants contribute to tumorigenesis by specific mechanisms. Furthermore, the results obtained by using the pLTR17p53 transfectants imply that some truncated molecules may overcome the effects of wild-type p53 to contribute to malignancy.
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PMID:Functional characterization in vivo of mutant p53 molecules derived from squamous cell carcinomas of the head and neck. 904 83

Survival in squamous cell carcinoma of the head and neck (HNSCC) was compared with overexpression and mutation of the p53 gene. Archival tissue from 77 tumours was analysed for protein expression using immunohistochemistry (IHC) with the monoclonal antibody Do-7, and for the presence of mutation in exons 5-8 using single-stranded conformation polymorphism (SSCP), followed by DNA sequencing in SSCP-positive cases. p53 expression was scored as high (>70% nuclei stained) in 25 (32%) tumours, as intermediate (10-70% nuclei stained) in 19 (25%) tumours and as low (<10% nuclei stained) in 33 (43%) tumours. Twelve (18%) tumours exhibited gene mutation (ten missense and two nonsense mutations) and an additional five tumours contained changes that could not result in amino acid substitution or protein truncation. There was no correlation between gene expression and mutation, mutations being equally frequent in tumours with either high (4/25), intermediate (4/19) or low protein expression (4/33). Fifty-eight patients were eligible for survival analysis. There was a strong correlation between p53 mutation and cause-specific survival; median survival among mutated cases was 12.5 months compared with >160 months among non-mutated patients (P < 0.005). There was no correlation between p53 overexpression and survival. The results suggest that p53 mutation status is an important prognostic factor in HNSCC, and that IHC analysis of protein overexpression is an inadequate measure of gene mutation in these tumours.
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PMID:p53 mutation, but not p53 overexpression, correlates with survival in head and neck squamous cell carcinoma. 979 55

Molecular studies have revealed that microsatellite instability and loss of heterozygosity occurred in head-and-neck cancer, suggesting the involvement both of suppressor and of mutator pathways in head-and-neck carcinogenesis. There is evidence for relations between tumor phenotype and clinical parameters. Indeed, replication-error phenotype, characterized by microsatellite instability, was associated with decreased sensitivity to chemotherapeutic agents in cell lines. Loss of heterozygosity is a frequent mechanism of inactivation of tumor-suppressor genes, which might be implicated in resistance to chemotherapy. In head-and-neck cancer, chemosensitivity is inconstant, and no marker is available to predict response to treatment. In order to evaluate the role of tumor phenotype on resistance to chemotherapy, we analyzed 56 primary head-and-neck squamous-cell carcinomas collected at time of diagnosis and a sub-group of 23 resistant tumors collected after chemotherapy at 22 microsatellite loci. At time of diagnosis, only one tumor showed MSI-H phenotype. Loss of heterozygosity (LOH) was observed in 75% of tumors, indicating the dominant role of the suppressor in comparison with the mutator pathway in HNSCC carcinogenesis. No change in microsatellite patterns was observed after treatment, suggesting that chemotherapy did not select mismatch-repair-deficient clones. Univariate analyses showed that LOH at 9p or 17p was significantly associated with drug resistance. In a multivariate analysis, only LOH at 17p remains predictive of low response to chemotherapy, with a relative risk of 3.7 and 95% CI of 1.1-13, indicating that p53 alterations could play a role in chemotherapy resistance in HNSCC. Int. J. Cancer (Pred. Oncol.) 84:410-415, 1999.
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PMID:Microsatellite analysis and response to chemotherapy in head-and-neck squamous-cell carcinoma. 1040 95

Sixty-nine cases of head and neck squamous cell carcinoma were examined by immunohistochemistry for p53 and chromosome in situ hybridization for chromosome 9 and 17 to determine the relationship between p53 expression and polysomies of chromosome 9 and 17 with the development of a second primary tumor as well as recurrence of primary tumor of head and neck squamous cell carcinoma. We found early expression of p53 in the normal and premaligant lesions adjacent to tumor which was associated with a gradual increase in the fraction of positive nuclei as well as numbers of cancer. We also found statistically significant increments of polysomies of chromosome 9 and 17 in terms of the polysomy index seen through the histologic changes occurring during multistep tumorigenesis. Our results could not demonstrate statistically significant correlation between p53 expression and PI 9 and 17 in tumorigenesis. Interestingly, however, there was a strong correlation between p53 expression and second primary tumor as well as recurrence of primary tumor. The p53 expressed group had a seven fold increased incidence in developing second primary tumor and a two and a half times increased incidence for recurrence of primary tumor, compared to the non-expressed group. We conclude that p53 expression and polysomies of chromosome 9 and 17 have an important role in multistep tumorigenesis in HNSCC. There was no significant correlation between p53 expression and polysomies of chromosome 9 and 17. However, the expression of p53 was statistically significant for association with second primary tumor and recurrence of primary tumor of head and neck squamous cell carcinoma.
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PMID:P53 expression and polysomies of chromosome 9, 17 in head and neck cancer prognosis. 1044 96

The genetic and functional status of the p53 gene may be an important factor in guiding therapeutic strategies for patients with cancer. The purpose of this study was to determine whether p53 immunohistochemistry (IHC) accurately reflects the mutational status of the p53 gene and to determine whether p53 IHC independently predicts tumor responsiveness to radiation therapy for patients with HNSCC. p53 IHC was performed using the monoclonal antibody DO7 on tumors from 85 patients with HNSCC treated with primary or adjuvant radiation. The p53 status in all of these tumors was previously assessed by direct sequence analysis of exons 5 through 9: 49 tumors were p53 wild-type, and 36 harbored p53 gene mutations. All patients were well characterized with respect to locoregional recurrence, distant spread, and survival. Positive p53 staining was observed in 53 of the 85 cases (62%). Only 27 (51%) of these 53 IHC-positive cases harbored gene mutations in exons 5 through 9; 23 (72%) of the 32 IHC-negative cases did not harbor mutations. The overall correlation rate between IHC and sequencing was 59% (P < .04, chi2). Discordant results were observed for 35 (41%) cases, including 26 IHC-positive cases and 9 IHC-negative cases. In 7 of 9 cases, false-negative staining was due to a nonsense or splice-site mutation. p53 IHC was not predictive of overall survival (P = .37) or disease-free survival (P = .95). In a sizable number of cases, p53 IHC does not reflect the mutational status of the p53 gene. Specific types of alterations (eg, truncating mutations) and other factors may contribute to this poor correlation. Moreover, p53 IHC does not appear to be an independent predictor of tumor responsiveness to radiation in patients with HNSCC.
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PMID:Immunohistochemical detection of p53 protein accumulation in head and neck cancer: correlation with p53 gene alterations. 1053 71

We investigated the prognostic significance of p53-gene mutation (exon 5-9) and bcl-2-protein expression in primary squamous-cell carcinoma of the head and neck (HNSCC) treated by curative radiotherapy (RT). Primary squamous-cell carcinomas for analysis were obtained from 85 consecutive head-and-neck-cancer patients, with complete follow-up data. We detected bcl-2 protein in 24% (20/85) of HNSCC studied; 38 (45%) of the 85 tumours had cells bearing p53 mutations. A strong association was observed between tobacco exposure and bcl-2-protein expression (p = 0.003), an association also evident in those patients who had a p53-mutated carcinoma (p = 0.049). Moreover, we found that most of the bcl-2-positive cancers (70%) were also mutated in the p53 gene (p = 0.010). In univariate and in multivariate analyses, the simultaneous detection of bcl-2 expression and a p53-gene mutation in a tumour biopsy specimen was associated with greater risk of locoregional failure (p = 0.002 and 0.001 respectively) and worse survival (p = 0. 045 and 0.033) within 5 years in HNSCC patients treated by RT. The present study shows a cumulative prognostic value of simultaneous detection of bcl-2 over-expression and p53-gene aberration in some primary HNSCC treated with conventional RT, and provides further evidence for cross-talk between p53 and bcl-2, suggesting that these genes are important determinants of radiation-induced apoptosis, thereby modulating resistance to RT. Int. J. Cancer (Pred. Oncol.) 84:573-579, 1999.
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PMID:Cumulative prognostic value of p53 mutations and bcl-2 protein expression in head-and-neck cancer treated by radiotherapy. 1056 1

Although clonogenic or divisional death is the main mechanism by which DNA-damaging agents demonstrate antitumor activity, recent data indicate that strategies specifically designed to trigger apoptosis may also prove to be useful antitumor agents. Protein kinase C (PKC) isoenzymes are involved in the regulation of cell proliferation, differentiation, and survival. Whereas pharmacological inhibition of PKC activity triggers apoptosis in most mammalian cells, cell line and tissue differences in sensitivities to these inhibitors remain. Whereas PKC inhibitors have potential as antitumor agents, issue of kinase specificity and solubility have remained obstacles to their clinical use. In this report, we investigated the antitumor activity of the PKC inhibitor chelerythrine chloride (chelerythrine), a selective inhibitor of group A and B PKC isoforms. Chelerythrine exhibited cytotoxic activity against nine human tumor cell lines tested in vitro. On the basis of the finding that radioresistant and chemoresistant squamous cell carcinoma lines (HNSCC) undergo apoptosis rapidly after treatment with chelerythrine in vitro, we assessed the effects of this agent on p53-deficient SQ-20B HNSCC cells in vivo. The results demonstrate that chelerythrine treatment of nude mice bearing SQ-20B is associated with significant tumor growth delay. Significantly, treatment with chelerythrine resulted in minimal toxicity. These findings demonstrate a potential for chelerythrine as an antitumor drug against squamous cell carcinoma.
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PMID:In vitro and in vivo activity of protein kinase C inhibitor chelerythrine chloride induces tumor cell toxicity and growth delay in vivo. 1069 May 61

We have identified a new human p53 homologue, p40 (p51/p63). This gene was mapped to the distal arm of 3q and was found to be essential for normal epithelial development. We used microsatellite and FISH analyses to search for genetic alterations of p40 in primary HNSCC. A more precise localization of p40 was completed using 6 known markers on 3q and a newly isolated microsatellite marker within the p40 gene. We also determined the genomic organization of the p40 gene using human YAC and BAC clones. Microsatellite analysis revealed that 14 of 26 (54%) primary HNSCC had allelic imbalance in at least 1 of the 7 microsatellite loci. However, FISH analysis with a p40 probe showed that a majority of HNSCC had an increased copy number of the locus regardless of allelic status. Thus, overrepresentation of the p40 locus may play an important role in the development of HNSCC.
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PMID:Frequent gain of the p40/p51/p63 gene locus in primary head and neck squamous cell carcinoma. 1079 91


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