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

Chemoprevention may be one way to prevent lung cancer in smokers who are motivated to quit but cannot stop. The approach to chemoprevention of lung cancer described in this article is based on an understanding of the lung carcinogens present in tobacco smoke. The available data indicate that the compounds in cigarette smoke most likely involved in the induction of lung cancer in humans are the complex of polynuclear aromatic hydrocarbons typified by benzo[a]pyrene (B[a]P) and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). A large number of compounds are now available that inhibit lung tumorigenesis by B[a]P or NNK in rodents. Inhibition of NNK-induced lung carcinogenesis by phenethyl isothiocyanate (PEITC) and inhibition of B[a]P-induced lung carcinogenesis by benzyl isothiocyanate (BITC) are discussed as examples. Studies with PEITC in rodents clearly demonstrate that it inhibits NNK-induced lung tumorigenesis by inhibiting the metabolic activation of NNK. Similar changes appear to occur in humans according to data generated in smokers who ate watercress, a source of PEITC. It is likely that mixtures of chemopreventive agents with activity against carcinogens in tobacco smoke, such as NNK and B[a]P, will be useful in chemoprevention of lung cancer in smokers. Furthermore, there is a need to develop suppressing agents for lung cancer that might be applicable in both smokers and ex-smokers.
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PMID:Approaches to chemoprevention of lung cancer based on carcinogens in tobacco smoke. 925 87

Mouse inbred strains with inherited predisposition and resistance to lung cancer provide a tool for the dissection of the complex genetics of this disease. In the present report, we have crossed the BALB/c with the SWR/J strain and performed whole-genome scanning for loci affecting lung tumor development in their F2 progeny. Both parental strains carry the pulmonary adenoma susceptibility 1 (Pas1) locus, a major locus affecting predisposition to lung cancer in mice. On distal chromosome 18 and on centromere of chromosome 6, we have mapped two pulmonary adenoma resistance loci (Par2 and Par4, respectively), which reduce lung tumor multiplicity strongly, up to 15-fold. Par2 and Par4, however, do not affect lung tumor size, which is instead controlled by an additional locus that we have mapped on the central region of chromosome 4. We designated this locus as "pulmonary adenoma progression 1" (Papg1), because it specifically modifies lung tumor size but not multiplicity. The present results, therefore, provide evidence for the existence of cancer modifier loci acting on specific stages of lung tumorigenesis.
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PMID:Genetic mapping of lung cancer modifier loci specifically affecting tumor initiation and progression. 933 Oct 67

Inherited predisposition to lung cancer is a phenotypic trait shared by different mouse inbred strains that show either a high or an intermediate predisposition. Other strains are instead genetically resistant. The Pas1 locus is the major determinant of lung cancer predisposition in the A/J strain (Gariboldi et al. 1993). To define the determinants of susceptibility to lung tumorigenesis in the highly susceptible SWR/J and in the intermediately susceptible BALB/c mice, we analyzed (BALB/c x SWR/J)F2 and (BALB/c x C3H/He)F2 crosses by genetic linkage experiments. The present results provide unequivocal evidence that the same Pas1/+ allele that leads to lung cancer predisposition is shared by A/J, SWR/J, and BALB/c strains. The intermediate susceptibility of the BALB/c strain would result by interaction of Pas1 locus with lung cancer resistance loci.
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PMID:Pas1 is a common lung cancer susceptibility locus in three mouse strains. 933 90

Allelic loss of chromosome 9p21 is common in small cell lung cancer (SCLC), but inactivation of the tumor suppressor gene CDKN2a is rare, implying the existence of another target gene at 9p21. A recent deletion mapping study of chromosome 9p has also identified a site of deletion in non-small cell lung cancer (NSCLC) centered around D9S126. The Hel-N1 (human elav-like neuronal protein 1) gene encodes a neural-specific RNA binding protein that is expressed in SCLC. We have mapped this potentially important gene in lung tumorigenesis to within 100 kb of the D9S126 marker at chromosome band 9p21 by using homozygously deleted tumor cell lines and fluorescence in situ hybridization to normal metaphase spreads. Hel-N1 is, therefore, a candidate target suppressor gene in both SCLC and NSCLC. We have determined the genomic organization and intron/exon boundaries of Hel-N1 and have screened the entire coding region for mutations by sequencing 14 primary SCLCs and cell lines and 21 primary NSCLCs preselected for localized 9p21 deletion or monosomy of chromosome 9. A homozygous deletion including Hel-N1 and CDKN2a was found in a SCLC cell line, and a single-base polymorphism in exon 2 of Hel-N1 was observed in eight tumors. No somatic mutations of Hel-N1 were found in this panel of lung tumors. Hel-N1 does not appear to be a primary inactivation target of 9p21 deletion in lung cancer.
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PMID:Genomic organization and mutation analysis of Hel-N1 in lung cancers with chromosome 9p21 deletions. 939 60

DT-diaphorase (EC 1.6.99.2) is a flavoprotein that catalyses two-electron reduction of quinones, quinone imines, and nitrogen oxides. It is a Phase II detoxifying enzyme that can detoxify chemically reactive metabolites, and may be important in an early cellular defense against tumorigenesis. DT-diaphorase is also an activating enzyme for bioreductive antitumor agents like mitomycin C (MMC) and EO9. DT-diaphorase is induced in many tissues by a wide variety of compounds including dithiolethiones and isothiocyanates. Dithiolethiones are chemoprotective agents against a variety of chemical carcinogens in animal models, and the dithiolethione analogue, oltipraz, is currently in Phase I and Phase II clinical chemoprevention trials. Similarly, the isothiocyanate derivative, sulforaphane, blocks the formation of carcinogen-induced mammary tumors in rats. The low toxicity of these inducers of DT-diaphorase makes them suitable for use as chemopreventive agents in high-risk individuals. Cells with elevated DT-diaphorase levels are generally more sensitive to bioreductive antitumor agents. Thus, we suggested that the antitumor efficacy of bioreductive agents can be enhanced by selective induction of DT-diaphorase in tumor cells compared with normal cells. We showed that 1,2-dithiole-3-thione (D3T) can increase the level of DT-diaphorase activity and the cytotoxic activity of bioreductive agents in mouse lymphoma cells without increasing these activities in normal mouse marrow cells. D3T also increased DT-diaphorase activity in 24 of 33 human tumor cell lines representing nine tissue types with no obvious relationships between the tumor type, or the base level of DT-diaphorase activity, and the ability to increase enzyme activity. A series of dithiolethione analogues and dietary components were also shown to be good inducers of DT-diaphorase in human tumor cells. D3T increased DT-diaphorase activity in normal human bone marrow and kidney cells but the increases were small in these cells. Combination treatment with D3T and EO9 increased cell kill in HL-60 human leukemia cells compared with EO9 alone, but had no effect on EO9 toxicity in normal human kidney cells. Similarly, D3T increased tumor cell kill by EO9 in H661 human lung cancer cells and by MMC in T47D human breast cancer cells. Thus, inducers of DT-diaphorase may play an important role in cancer chemoprevention programs and may also be useful in enhancing the antitumor efficacy of bioreductive agents.
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PMID:Induction of DT-diaphorase in cancer chemoprevention and chemotherapy. 940 43

Immortalization and tumorigenic transformation of many human cell types, including human uroepithelial cells (HUCs), are frequently associated with loss of genetic material from the short arm of chromosome 3 (3p). In addition, losses of 3p have been observed in many human cancers including renal cell carcinoma, lung cancer, breast cancer, and bladder cancer. Genetic studies suggest that there are at least two regions on 3p in which tumor suppressor genes might be located, but the precise location of these genes is not known. We studied chromosome 3 losses that were specifically associated with immortalization of five independent human papilloma virus 16 (HPV16) E6- or E7-transformed HUCs. Cytogenetic analysis showed that the smallest common region of deletion was 3p14.1-->14.2. Fluorescence in situ hybridization using a 3p13-->14-specific yeast artificial chromosome (YAC) contig showed the precise localization of the breakpoints to be in 3p13 and 3p14.2, thus defining the smallest common overlap of 3p deletions in HPV16 E6- or E7-immortalized HUCs. These results suggest the presence in this region of genes involved in the control of senescence in vitro and possibly tumorigenesis in vivo.
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PMID:Minimal deletion of 3p13-->14.2 associated with immortalization of human uroepithelial cells. 944 40

Lung cancer is the leading and second-leading cause of cancer deaths among women and men in Taiwan, respectively. However, the molecular mechanisms involved in lung tumorigenesis in Taiwan remain poorly defined. A study that analyzed the mutation spectrum of the p53 tumor suppressor gene in 35 female lung cancer patients in Hong Kong showed that a high proportion of the mutations observed were deletions, suggesting the possible involvement of a distinct mutagenic factor(s) in Chinese female lung cancer patients (Y. Takagi et al., Cancer Res., 55: 5354-5357, 1995). Therefore, to gain insight into the role of the p53 tumor suppressor gene and possible etiological factors in lung tumorigenesis in Taiwan, we investigated the mutation spectra of exons 4-11 in the p53 tumor suppressor gene of 60 lung cancer patients in Taiwan. These data were also correlated with clinical pathological characteristics of patients. Lung tumors were surgically resected, genomic DNA was isolated, and their mutation spectra were examined using PCR/single-strand conformational polymorphism analysis and direct sequencing. The frequency of p53 gene mutation was 18% (11 of 60). However, distinct patterns of p53 gene mutation were observed. Seven of 11 mutations detected (64%) were deletions of 1-12 bp at G:C bp or at bp in the immediate vicinity of repetitive sequences and/or tandem repeat sequences. In addition, two patients (2 of 11, 18%) exhibited nonsense mutations. In contrast to the frequent occurrence of missense mutations in the p53 gene reported in the literature, the majority (82%) of the mutations in lung cancer patients in Taiwan were nonmissense mutations, ie., deletions and nonsense mutations. Immunohistochemical staining indicated that p53 mutations including non-in-frame deletions and nonsense mutations all resulted in no expression of p53 protein. Notably, mutations occurred more frequently in patients suffering from squamous cell carcinoma (SQ). Nine of 31 SQ patients (29%) exhibited deletions or nonsense mutations, suggesting that deletions and nonsense mutations in the p53 gene are involved in the formation of SQ in Taiwan. In addition, mutations occurred more frequently in patients with stage III or IV lung cancer. However, mutations were not correlated with patients' smoking habits. Our data suggest that p53 gene mutation involved in the formation of SQ and distinct environmental factor(s) and/or genetic factor(s) that induced specific short deletions in repeat sequences may be involved in lung tumorigenesis in Taiwan.
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PMID:High frequency of deletion mutations in p53 gene from squamous cell lung cancer patients in Taiwan. 944 13

All-trans retinoic acid (RA) has been shown to inhibit cell proliferation while increasing neuroendocrine differentiation in small cell lung cancer (SCLC) cells. RA and related compounds are rapidly becoming integrated into clinical trials to prevent lung cancers and other aerodigestive neoplasms. We found that expression of gastrin releasing peptide (GRP), which can promote lung tumorigenesis in model systems, was increased by RA in SCLC cells which have functional retinoid signaling. In SCLC cells that possess functional GRP receptors, ectopic expression of RARc increased GRP expression and augmented cloning efficiency, demonstrating that these maneuvers result in biologically active GRP. SCLC cells with defects in RA pathway signaling did not efficiently induce GRP upon RA exposure. In these cells, transfection of RARs rendered the cells competent to induce GRP upon RA exposure. These data show that activation of intact retinoid signaling by RA can induce GRP, a growth factor that can act as a tumor promoter. Our findings suggest the possibility that retinoids may increase, rather than decrease, lung cancer risks in some individuals.
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PMID:Induction of gastrin releasing peptide by all-trans retinoic acid in small cell lung cancer cells. 946 88

The expression of p53 protein was evaluated immunochemically in cancer tissue, preneoplastic lesions and normal bronchial mucosa obtained during diagnostic bronchoscopy from 53 patients with lung cancer and 12 patients with benign lung diseases. In lung cancer patients, positive p53 staining was detected in 26/53 (49%) of the tumour specimens. In preneoplastic lesions p53 positive staining was found in 8 of 24 (33.3%) squamous metaplasia, 1 of 4 hyperplasia and 1 of 3 dysplasia lesions. In the same group of patients, 12 cases were found with positive p53 cells in normal bronchial mucosa. In patients with benign diseases, positive p53 staining was found in 1 of 4 cases with squamous metaplasia and in one normal mucosa. Our results provide evidence that somatic genetic alterations may occur in early stages of lung tumorigenesis, raising the possibility that molecular analyses is useful in the early diagnosis of precancerous lesions of the bronchial mucosa, and results indicate that p53 expression can be studied in small tissue specimens obtained during bronchoscopy.
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PMID:Immunohistochemical detection of p53 protein in neoplastic, preneoplastic and normal bronchial mucosa specimens obtained during diagnostic bronchoscopy. 953 90

The activity of chemical carcinogens is a complex balance between metabolic activation by cytochrome P450 monooxygenases and detoxification by enzymes such as glutathione S-transferase (GST). Regulation of these proteins may have profound effects on carcinogenic activity, although it has proved impossible to ascribe the observed effects to the activity of a single protein. GstP appears to play a very important role in carcinogenesis, although the precise nature of its involvement is unclear. We have deleted the murine GstP gene cluster and established the effects on skin tumorigenesis induced by the polycyclic aromatic hydrocarbon 7, 12-dimethylbenz anthracene and the tumor promoting agent 12-O-tetradecanoylphorbol-13-acetate. After 20 weeks, a highly significant increase in the number of papillomas was found in the GstP1/P2 null mice [GstP1/P2(-/-) mice, 179 papillomas, mean 9.94 per animal vs. GstP1/P2(+/+) mice, 55 papillomas, mean 2.89 per animal, (P < 0.001)]. This difference in tumor incidence provides direct evidence that a single gene involved in drug metabolism can have a profound effect on tumorigenicity, and demonstrates that GstP may be an important determinant in cancer susceptibility, particularly in diseases where exposure to polycyclic aromatic hydrocarbons is involved, for instance in cigarette smoke-induced lung cancer.
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PMID:Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases. 956 Feb 66


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