Interferon regulatory factor 1 tryptophan 11 to arginine point mutation abolishes DNA binding.
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Interferon regulatory factor-1 (IRF-1) is a transcriptional activator of genes induced by a variety of cytokines and growth factors. Defects in IRF-1 occur frequently in human cancers and may contribute to tumorigenesis. The IRF family of transcription factors share invariant tryptophan residues that have been proposed to function by orienting the DNA contacting residues of IRF-1 with the DNA core sequence of the IRF element. Here we describe a point mutation in IRF-1 that converts the tryptophan at codon 11 to arginine (W11R). The IRF-1 (W11R) mutation abolishes IRF-1 DNA binding and transactivating activities demonstrating the critical role of this invariant tryptophan in IRF-1 function. (+info)
The expression of p73 is increased in lung cancer, independent of p53 gene alteration.
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p73 gene, a new p53 homologue, has been identified: it supposedly acts as tumour suppressor gene in neuroblastoma. To clarify whether p73 might be involved in lung carcinogenesis, we examined p73 expression in resected lung cancer and paired normal lung in 60 cases using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). We also examined p73 gene status in three representative cases using Southern blot, and p53 gene alteration in 49 cases using PCR-single-strand conformation polymorphism (PCR-SSCP) and direct sequence. In 87% of the cases (52/60) p73 expression in tumour was more than twice as high as that in paired normal lung tissues, and the difference between p73 expression in tumour and normal lung tissue was significant (P < 0.0001). However, Southern blot analysis revealed that none of the cases showed p73 gene amplification. Compared with clinicopathological characteristics, p73 expression correlates significantly with histological differences and age of patient, independently (P < 0.05). Concerning p53 gene status, 43% (21/49) showed p53 gene alteration, but there was no correlation between p73 overexpression and p53 gene alteration. Our results suggest that need for further functional analysis of the role of p73 in lung carcinogenesis. (+info)
Associations among telomerase activity, p53 protein overexpression, and genetic instability in lung cancer.
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Genomic instability is a driving force for tumorigenesis. p53 and telomerase play central roles in maintaining genomic integrity. The purpose of this study was to assess the associations among p53 protein overexpression, telomerase activity and genetic instability in lung cancer. We found that telomerase activity was detectable in 80% of 100 lung tumours, but only 7.7% of 91 paired adjacent normal tissues. p53 protein was overexpressed in 63% of the tumours but only 2% of the normal tissues. p53 was overexpressed in 56 of the 80 (70%) tumour tissues with telomerase activity but only seven of the 20 (35%) without telomerase activity. p53 protein overexpression carried a 6.7-fold (95% confidence interval, 1.7-27.7) increased risk for positive telomerase activity after adjustment by age, sex, ethnicity, smoking status and family history of lung cancer. The mean in vitro bleomycin-induced breaks per cell (a marker of cancer susceptibility) was significantly higher (0.92) for patients who overexpressed p53 in lung tumour tissue than that for patients with no detectable p53 expression in lung tumour tissue (0.65). Our data suggest that p53 protein overexpression may be common in individuals genetically susceptible to carcinogen exposure. p53 status may be related to telomerase expression. (+info)
Identification of cytosolic aldehyde dehydrogenase 1 from non-small cell lung carcinomas as a flavopiridol-binding protein.
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The synthetic flavone flavopiridol can be cytostatic or cytotoxic to mammalian cells, depending on the concentration of the drug and the duration of exposure. It has been shown to inhibit the cyclin-dependent kinase (CDK) family of cell cycle regulatory enzymes. However, the existence of additional potential targets for drug action remains a matter of interest to define. To identify cellular targets, flavopiridol was immobilized. CDKs, particularly CDK 4, bound weakly to immobilized flavopiridol when ATP was absent but not in its presence. Two proteins with molecular weights of 40 kDa and 120 kDa had high affinities to the immobilized flavopiridol independent of the presence of ATP. They were present in all cell lines analyzed: cervical (HeLa), prostate and non-small cell lung carcinoma (NSCLC) cell lines. A 60-kDa protein, which was present only in NSCLC cells and bound similarly well to immobilized flavopiridol, was identified as cytosolic aldehyde dehydrogenase class 1 (ALDH-1). The level of this protein correlated with the resistance of NSCLC cell lines to cytotoxicity caused by 500 nM flavopiridol but not higher flavopiridol concentrations. Despite binding to ALDH-1, there was no inhibition of dehydrogenase activity by flavopiridol concentrations as high as 20 microM and flavopiridol was not metabolized by ALDH-1. The results suggest that high cellular levels of ALDH-1 may reduce cytotoxicity of flavopiridol and contribute to relative resistance to the drug. This is the first report that flavopiridol binds to proteins other than CDKs. (+info)
Standard- and high-dose etoposide, ifosfamide, carboplatin, and epirubicin in 107 patients with non-small-cell lung cancer: a mature follow-up report.
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BACKGROUND: We conducted a phase I-II trial to assess the activity of standard-dose (SDC) and high-dose chemotherapy (HDC) with etoposide, ifosfamide, cis/carboplatin, and epirubicin (VIP-E, VIC-E) in 107 patients with limited-stage (LS, stage I-IIIB) and extensive stage (ES, stage IV) non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Updated results of a previously published trial are presented. RESULTS: Response rates and survival after VIP-E were comparable to those of other standard-dose combination chemotherapies in NSCLC. Treatment-related mortality (TRM) in SDC was 3% in LS-NSCLC, and 8% in ES-NSCLC. TRM was 4% in patients selected for HDC by response rate and performance score. Five-year survival in LS-NSCLC was 12% after SDC, and 18% after HDC; it was 0% for both treatment protocols in ES-NSCLC. CONCLUSIONS: The activity of VIP-E SDC and VIC-E HDC is not superior to that of established protocols in the treatment of NSCLC. In view of the toxicity and TRM associated with this protocol, less aggressive regimens should be preferred for most patients. Whether selected patients with chemosensitive disease could benefit from VIP-E SDC and/or VIC-E HDC in an adjuvant or neo-adjuvant setting could not be determined within the scope of this study. (+info)
Molecular epidemiological study of non-small-cell lung cancer from an environmentally polluted region of Poland.
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The p53 mutation spectrum can generate hypotheses linking carcinogen exposure to human cancer. Although it is well-documented that tobacco smoking is a major cause of lung cancer, the contribution of air pollution is less well-established. We determined the molecular and immunohistochemical changes (p53 gene mutations, p53 protein accumulation and WAF1 protein expression) and genetic polymorphisms of GSTM1, CYP1A1 and CYP2D6 genes in a case series of non-small-cell lung cancers from Silesia. This region of southern Poland is highly industrialized with considerable environmental pollution. More than 50% of lung cancers (90/164) contained p53 mutations and 75% showed the combined alteration of the p53 gene and protein accumulation. Males occupationally exposed to coal-derived substances showed a relatively high frequency of squamous and large-cell carcinomas, relatively frequent mutations in codon 298 of p53 and a low frequency of p53 immunohistochemically positive tumours. Codon 298 GAG-->TAG mutations have rarely been found in lung cancers in other populations. We found no correlation between WAF1 protein expression and mutations in the p53 gene or p53 protein accumulation. No statistically significant relationship was found between p53 mutations and GSTM1, CYP1A1, CYP2D6 genotypes. Never smokers with lung cancers from Silesia had a higher frequency of G:C-->T:A transversions than previously reported of the p53 mutation spectrum in never smokers (6/15 vs 4/34; P = 0.06 by chi2). These data are a tentative indication that occupational and environmental exposure to polycyclic aromatic hydrocarbons, such as benzo(a)pyrene, in polluted air contributes to the molecular pathogenesis of lung cancer in never smokers. (+info)
How many tumor suppressor genes are involved in human lung carcinogenesis?
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To date, only a limited number of tumor suppressor genes have been identified as being inactivated in lung cancer. The p53 and RB genes are frequently inactivated by genetic alterations such as chromosomal deletions and loss-of-function mutations, while the p16 gene is inactivated not only by genetic alterations but also by transcriptional silencing due to hypermethylation. Recently, it was shown that the FHIT gene encompassing the chromosomal fragile site, FRA3B, is also inactivated in a large proportion of lung cancers. Several lines of evidence indicate the presence of additional tumor suppressor genes involved in lung carcinogenesis. Lung cancer cells often show deletions at multiple chromosomal regions, and deletion mapping studies have defined more than 30 regions dispersed on 21 different chromosome arms as candidate tumor suppressor loci. Several chromosomal regions hypermethylated in lung cancer cells and a number of chromosomal fragile sites have been mapped to the regions deleted in lung cancer. These chromosomal loci can harbor unknown tumor suppressor genes inactivated in lung cancer. Studies on the inherited susceptibility to lung cancer in mice have also indicated the presence of additional tumor suppressor genes for lung cancer. Further analyses of these loci should elucidate how many tumor suppressor genes are involved in human lung carcinogenesis. Molecular and functional analyses of those genes will make it possible to fully understand the molecular mechanism of lung carcinogenesis. (+info)
K-ras oncogene mutation as a prognostic marker in non-small cell lung cancer: a combined analysis of 881 cases.
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The treatment of non-small cell lung cancer (NSCLC) remains unsatisfactory, with most patients succumbing to metastatic disease within 5 years of diagnosis. Improved selection of patients for aggressive adjuvant therapy may contribute to improved survival. Mutation of the k-ras oncogene is considered a potentially clinically useful prognostic biomarker for this purpose. This report presents the results of a meta-analysis performed to determine whether the existing data support such a role for k-ras mutations in NSCLC. Two year survival data derived from 881 NSCLC patients in eight published studies were analyzed using a general variance-based meta-analytical method employing confidence intervals. The outcome of interest was a summary relative risk (RR(s)) reflecting the risk of death at 2 years associated with k-ras mutation-positive versus k-ras mutation-negative disease. Prior to calculation of RR(s), analysis for heterogeneity showed Q to equal 15.52 (7 df, P = 0.03). This indicated heterogeneity across the analyzed studies in terms of their estimate of effect. Possible sources of heterogeneity were identified and included selection bias and various other sources of uncontrolled confounding. Although a RR(s) of 2.35 (95% CI = 1.61-3. 22) was found when all eight studies were combined (favoring a negative prognostic role for k-ras mutation), it is unclear whether the magnitude of the RR(s) would persist after adjusting for other well-established prognostic indicators (e.g. stage). The existing data suggest that k-ras mutation may be associated with shortened survival in NSCLC, although this finding awaits confirmation in well-designed multivariate analyses which adjust for the effect of known prognostic indicators. (+info)