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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper reviews mutational activation of ras oncogenes and inactivation of the p53 tumor suppressor gene in human lung cancer. We discuss the frequency, type, and location of mutations in these genes in relation to known etiological factors for lung cancer. The most studied examples of these are exposure to tobacco smoke, and to radon and asbestos fibers at work. We summarize data from our laboratory on K-ras and p53 mutations in fresh tissue samples from patients with resected primary lung carcinoma whose smoking and occupational histories were known. Most of the tumors examined were histologically non-small cell carcinoma (NSCLC), mainly of the squamous cell carcinoma and adenocarcinoma types. We compare the prevalence and nature of mutations in the two histological types of NSCLC.
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PMID:p53 and ras gene mutations in lung cancer: implications for smoking and occupational exposures. 762 Sep 45

A replication-defective and helper-independent recombinant p53 adenovirus was generated. The virus, Ad5CMV-p53, carries an expression cassette that contains human cytomegalovirus E1 promoter, human wild-type p53 cDNA, and SV40 early polyadenylation signal. Four human non-small-cell lung cancer cell lines representing differences in p53 configuration were used to evaluate the Ad5CMV-p53 virus. In the H358 cell line, which has a homozygous deletion of p53, the p53 gene was transferred with 97% to 100% efficiency, as detected by immunohistochemical analysis, when the cells were infected with Ad5CMV-p53 at a multiplicity of infection of 30 to 50 plaque-forming units/cell. Western blots showed that the p53 protein was expressed at a high level. The protein expression peaked at day 3 after infection and lasted for at least 15 days. Growth of the Ad5CMV-p53 virus-infected H358 cells was inhibited 79%, whereas that of noninfected cells or the cells infected with the control virus was not inhibited. Growth of cell line H322, which has a point mutation in p53, was inhibited 72% by Ad5CMV-p53, while that of cell line H460 containing wild-type p53 was less affected (28% inhibition). Tests in nude mice demonstrated that tumorigenicity of the Ad5CMV-p53-treated H358 cells was greatly inhibited. In a mouse model of orthotopic human lung cancer, the tumorigenic H226Br cells, with a point mutation in p53, were inoculated intratracheally 3 days before the virus treatment. Intratracheal instillation of Ad5CMV-p53 prevented tumor formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:High-efficiency gene transfer and high-level expression of wild-type p53 in human lung cancer cells mediated by recombinant adenovirus. 762 Dec 38

This study examined the sensitivity and specificity of serum auto-antibodies to p53 protein as a non-invasive marker of p53 genetic alterations or protein accumulation in lung cancer cases. A sensitive ELISA to detect serum p53 antibodies was developed and used to examine sera from 186 patients undergoing pulmonary surgery for a suspected lung cancer. Target antigens in ELISA were wild-type p53 protein and 5 peptides covering the N- and C-terminal parts of the protein. Sixteen sera were positive for serum p53 antibodies in both ELISAs and all were among the 136 patients with confirmed primary lung carcinoma. Of 50 patients with other pulmonary diseases, none had p53 antibodies. In 92 cancer patients exons 5 to 8 of the p53 gene were examined for mutations by denaturing gradient gel electrophoresis and direct sequencing of PCR products. Forty-seven tumours had a p53 mutation and 7 (15.2%) of these were positive for p53 antibodies. Two patients had serum antibodies but no detectable mutation in exons 5 to 8. Frequencies of p53 mutations and serum antibodies were higher in squamous cell carcinoma patients than in adenocarcinoma. Accumulation of p53 protein in tumour tissue was observed in 32 patients, but only 5 were positive for p53 antibodies. In conclusion, serum p53 antibodies were detected only in a proportion of lung cancer cases, but the majority were specifically associated with a detectable p53 mutation in the tumour.
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PMID:p53 antibodies in the sera of lung cancer patients: comparison with p53 mutation in the tumour tissue. 762 6

To investigate the relevance of the C-terminal domains of the human p53 tumor suppressor gene to its growth suppressive and transcriptional regulatory properties deletion mutants were generated which eliminated 30 (p53 delta 363), 60 (p53 delta 333) and 87 (p53 delta 306) amino acids from the C-terminus of the p53 protein. p53 delta 363 has lost the highly basic tail of the protein (residues 360-386). p53 delta 333 and p53 delta 306 lack the oligomerization domain (residues 320-360); p53 delta 306 has also lost the major nuclear localization signal of p53 (NLSI, residues 316-325). These mutants were assayed for transactivation from two p53 consensus binding sites and for transcriptional repression of two promoter systems in Calu6 lung cancer cells (p53 null). Moreover, their ability to inhibit cell growth in tumor cell lines with a defined p53 status was analysed. Deletion of the oligomerization domain correlated with significant loss of: (a) transactivation from a genomic sequence; (b) transcriptional repression; (c) the ability to inhibit colony formation. An intact NLSI was not a prerequisite for transactivation. p53 delta 363 behaved similarly to wt p53 in all the assays. We established an inducible expression system for p53 delta 363 in a human fibrosarcoma cell line known to be growth-suppressed by wt p53. The induction of p53 delta 363 expression also inhibited cell proliferation albeit to a lesser extent than wt p53. However, p53 delta 363 could upregulate WAF1/CIP1, GADD45 and MDM2 genes. Thus, the basis tail of p53 appears not to be required for the biological functions of the protein assayed.
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PMID:The basic carboxy-terminal domain of human p53 is dispensable for both transcriptional regulation and inhibition of tumor cell growth. 762 48

To investigate whether the high frequency of human papillomavirus infection in butchers may be linked to their higher than average incidence of lung cancer, we have examined lung cancers from 40 butchers and 26 controls for the presence of DNA from both HPV type 7, which is found almost uniquely in hand warts from butchers and fishermen, and for those HPV types associated with laryngeal and genital cancers. No HPV 7, and only a low frequency of HPV DNA was found, suggesting that HPV infection does not make an important contribution to the elevated levels of lung cancer in meat handlers. In addition, the frequency of p53 mutation was shown to be slightly lower than previously reported in lung cancers.
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PMID:Human papillomavirus DNA and TP53 mutations in lung cancers from butchers. 764 Feb 8

Although the short arm of chromosome 17, which contains the p53 gene, is frequently affected by loss of heterozygosity (LOH) in lung cancer, little is known about similar changes on the long arm. We found that LOH affected one or more of six loci along chromosome 17 in 59% of 102 informative non-small cell lung cancer (NSCLC) cases. Specifically, the frequency of LOH at 17q was 42%, approaching that at 17p (54%), and two distinct 17q regions were implicated. LOH at D17S4 on 17q was more frequent in adenocarcinomas than in squamous cell carcinomas, whereas squamous cell carcinomas had more LOH at 17p than at 17q, findings that indicate molecular genetic heterogeneity between the major NSCLC subtypes. In addition, LOH at 17q correlated with higher T stages and a significantly worse prognosis. In comparison, 25% of cases had mutations of p53 exons 5-8 but these were not associated with stage or survival. The data suggest that independent of p53, there are important tumor suppressor gene(s) on 17q that may influence NSCLC pathogenesis, progression, and survival.
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PMID:Loss of heterozygosity frequently affects chromosome 17q in non-small cell lung cancer. 767 Dec 34

In order to define the roles of the K-ras and p53 genes in the development of lung cancer, especially in young adults, we compared the clinicopathological features of the patients between younger (< or = 45 years, n = 47) and older (< 55 years, n = 50) groups. The gene alterations were examined by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method. The K-ras gene alterations were detected only in adenocarcinomas, and the p53 gene alterations in all histologic types of lung cancer. There were no significant differences in the frequency of both K-ras and p53 gene alterations between the younger and older groups (9 vs. 11%, 36 vs. 32%). In the younger group, but not in the older one, the percentage for smokers was significantly higher in the p53 gene alteration-positive group than for the negative group (65 vs. 30%). As to the prognosis, there were no significant differences between the p53 gene alteration-positive and -negative cases in both the younger and older groups as well as in all subjects, while a tendency of poorer prognosis was observed in K-ras gene alteration-positive cases than for the -negative ones with adenocarcinomas. These results suggest that (1) the K-ras and p53 gene alterations would have no special roles in terms of the lung carcinogenesis in young adults; (2) a positive relationship between smoking and p53 gene alteration would exist in young adults with lung cancer, and (3) K-ras gene alteration would become a prognostic factor in lung cancer.
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PMID:Studies on clinicopathological features of lung cancer patients with K-ras/p53 gene alterations: comparison between younger and older groups. 771 5

Rapid advances in cancer gene therapy are driven by an explosive development of gene transfer technology and a strong demand for effective alternatives to unsatisfactory conventional cancer therapies. Discovery of the genetic basis of cancer has indicated that cancer is a disease of genes. Among a variety of approaches to gene therapy of cancer, anti-oncogene and tumor suppressor gene therapy of cancer are the two strategies that aim at correcting genetic disorders of cancer. The potential effectiveness of these approaches is promised by their precise targeting at the mechanisms of the disease. Successful examples of human lung cancer animal models by applying anti-K-ras retrovirus and recombinant p53 adenovirus are reviewed. Future development of these approaches towards clinical application is also discussed.
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PMID:Anti-oncogene and tumor suppressor gene therapy--examples from a lung cancer animal model. 772 23

Non-small-cell lung cancer (NSCLC) prognosis is strictly related to well-established clinicopathological parameters which have unfortunately become insufficient in the prognostic evaluation of this type of cancer. As p53 and bcl-2 gene deregulations are frequently involved in several types of epithelial malignancies, we investigated the Bcl-2 and p53 protein expression in 91 and 101 cases of NSCLC respectively. The expression was then compared with established indicators of prognosis and biological behaviour of the tumours. No relationship was observed between Bcl-2 and either clinicopathological or biological parameters such as histology, grading, tumour status, nodal metastasis and proliferative activity evaluated by scoring proliferating cell nuclear antigen expression and Ki-67 immunoreactivity. However, the mean Bcl-2 expression was significantly lower in patients who developed metastasis during follow-up or died of metastatic disease (P = 0.006 and P = 0.01 respectively). Moreover, survival probability was higher in patients who expressed the Bcl-2 protein (P = 0.0002). In contrast with this, p53 protein accumulation was observed in tumours with metastatic nodal involvement (P = 0.02) or in patients who developed metastasis during follow-up (P = 0.01), although no correlation was found between p53 expression and overall survival. An inverse relationship was also found between Bcl-2 and the anti-oncogene protein product p53 (P = 0.01). Thus, a high proportion of NSCLCs express p53 and Bcl-2 proteins and their expression may have prognostic importance.
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PMID:Bcl-2 protein: a prognostic factor inversely correlated to p53 in non-small-cell lung cancer. 773 90

In preparation for a clinical trial of the recombinant p53 adenovirus Ad5CMV-p53 for the treatment of lung cancer, the potential adverse effects of Ad5CMV-p53 were assessed in vitro and in vivo. No infectious replication of Ad5CMV-p53 was detectable in HeLa cells infected with extracts from HeLa cells previously infected with Ad5CMV-p53. No Ad5CMV-p53 DNA replication was detected by 32Pi labeling in lung cancer cells infected with Ad5CMV-p53 at multiplicities of infection (moi) up to 1,000 pfu/cell (total of 5 x 10(9) pfu viruses). The infectivity and cytotoxicity of Ad5CMV-p53 were examined in vitro in normal human bronchial epithelial (NHBE) cells. At a moi of 50 pfu/cell, Ad5CMV-p53 infection and expression were detectable in 80% of the treated cells. The exogenous p53 protein was first detected by western blotting at 8 hr and peaked at 48 hr after infection. Growth of NHBE cells was not affected by Ad5CMV-p53 infection at a moi of 100 pfu/cell. The pathogenicity of Ad5CMV-p53 was assessed in BALB/c mice. The virus was given to four groups of mice by intratracheal injection at dosages from 10(7) to 10(10) pfu; a fifth group received phosphate-buffered saline alone. None of the viral injections proved to be lethal. Mild to moderate peribronchiolar and perivascular infiltration by mononuclear cells and lymphocytes, with patches of pneumonitis, was the most acute toxic effect detected by histologic analysis in the two high-dose groups. Immunohistochemical analysis of the same paraffin-embedded sections showed that infectivity and level of expression of p53 in lung tissue were dose-dependent. Our results demonstrate that Ad5CMV-p53 is a replication-defective virus that yields a relatively low degree of acute toxicity in mice; these data document a safety profile encouraging for clinical trials of Ad5CMV-p53 in the therapy of lung cancer.
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PMID:Safety evaluation of Ad5CMV-p53 in vitro and in vivo. 773 16


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