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

Etoposide, a podophyllotoxin derivative, has demonstrated antitumor efficacy in a number of human malignancies, including lymphomas, germinal tumors, and lung cancer (especially small cell). Etoposide's antineoplastic activity is achieved through DNA strand breakage, which likely results from the formation of a complex involving drug, DNA, and the DNA unwinding enzyme, topoisomerase II. The drug's steady state volume of distribution ranges from 5 to 17 L/m2, and it is highly bound to plasma protein with an average free plasma fraction of 6%. A number of etoposide metabolites have been confirmed or postulated. Several cell lines have been shown to acquire resistance to etoposide through membrane transport changes. Considerable intrapatient variability exists in pharmacokinetic parameters following intravenous (IV) and oral dosing. Approximately 30% to 40% of unchanged IV drug is excreted in the urine, whereas biliary excretion appears a minor route of drug elimination. The bioavailability of oral etoposide averages 50%, although wide variability exists both among and within different patients. Bioavailability decreases as the dose of oral etoposide is increased. Several recent studies have attempted to correlate etoposide plasma concentrations with toxicity (primarily myelosuppression) in hopes of using this information to optimize drug dosing.
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PMID:Etoposide pharmacology. 149 25

Tobacco-specific nitrosamines are derived from nicotine and related tobacco alkaloids and can be detected in tobacco products as well as in mainstream and sidestream smoke. Two of them, N-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, are strong carcinogens in laboratory animals. Because of its organospecificity for the lung, the latter is considered to be a causative factor in tobacco-related human lung cancer. Upon metabolic activation both nitrosamines give rise to a common reactive intermediate binding to macromolecules such as DNA and haemoglobin and hydrolysing to 4-hydroxy-1-(3-pyridyl)-1-butanone. Because of easy access to large quantities of haemoglobin from blood samples, it is most suitable for biomonitoring human exposure to tobacco-specific nitrosamines. A highly sensitive analytical method for determination of femtogram amounts of 4-hydroxy-1-(3-pyridyl)-1-butanone provides an approach to assess individual exposure to active and passive smoking.
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PMID:Tobacco-specific nitrosamines--metabolism and biological monitoring of exposure to tobacco products. 152 Oct 43

The induction of micronuclei was studied in human diploid fibroblasts incubated in the presence of the tobacco-specific nitrosamine NNK. We used four fibroblast strains having a high capacity of O6-alkylguanine DNA alkyltransferase (13.0-23.3 pmol O6-methylguanine repaired per 8 x 10(6) cells) and four strains that showed no detectable repair capacity. Incubation with NNK doubled the frequency of micronuclei in repair-deficient cells but failed to evoke any effect in the proficient cell strains. Control experiments were performed with the direct methylating agent MNNG and in the presence of inhibitors of either metabolic activation or alkyltransferase. The results showed that the genotoxicity of NNK is dependent on the relationship between its metabolic activation and the constitutive DNA repair. This supports earlier findings that low constitutive levels of O6-alkylguanine DNA alkyltransferase may increase susceptibility to lung cancer after exposure to DNA methylating agents.
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PMID:Determinants of a genotoxic effect of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in human diploid fibroblasts. 152 Oct 44

Dimethylarsinic acid (DMAA) administration induced the preferential increase of the heterochromatic area forming the inside of the interphase nucleus. A histopathological study of the lung and liver in mice after DMAA administration was carried out by transmission electron microscopy. Ultrastructural alterations in the endothelial nuclei of the alveolar wall were observed 12-48 h after administration. Heterochromatin tended to collect in a dense, compact mass lining the inner walls of the nucleus. A significant increase in heterochromatin induced by DMAA administration was observed by morphometric analysis. However, no substantial differences appeared in the sinusoidal endothelium of the liver. This study suggests that the much greater induction of morphological alterations, such as increased heterochromatin, in lung endothelial nuclei than in the liver might explain the high risk of lung cancer by arsenics, and that there may be a close relationship between heterochromatin alteration and DNA damages.
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PMID:Preferential increase of heterochromatin in venular endothelium of lung in mice after administration of dimethylarsinic acid, a major metabolite of inorganic arsenics. 154 28

Accumulating evidence indicates that lung cancer arises due to multiple genetic changes in both dominant oncogenes, such as ras, and tumor suppressor genes, such as p53. In this report we examined whether the wild-type p53 gene is able to suppress in vitro and/or in vivo cellular growth of lung cancer cell lines which carry multiple genetic abnormalities. Introduction of a wild-type p53 complementary DNA expression vector into lung cancer cell lines carrying either a homozygous deletion (NCI-H358) or a missense mutation (NCI-H23) in the p53 gene greatly suppressed tumor cell growth. In contrast, p53 expression vectors bearing lung cancer derived mutations affecting single amino acids had lost this growth suppressing ability.
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PMID:Wild-type but not mutant p53 suppresses the growth of human lung cancer cells bearing multiple genetic lesions. 155 36

Lung cancer is now the leading cause of excess mortality among smokers in the United States. The ability to identify smokers with the greatest risk of developing lung cancer would be an important step in reducing lung cancer mortality. Tobacco-specific nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N'-nitrosonornicotine are important carcinogens in tobacco smoke. These carcinogens require metabolic activation to exert their carcinogenic effects. Methods are described for the measurement of DNA and hemoglobin adducts formed by the metabolites of these nitrosamines. Preliminary evidence is presented that shows that a subpopulation of smokers have elevated levels of DNA and hemoglobin adducts of tobacco-specific nitrosamines. Further work is in progress to test the hypothesis that smokers with elevated levels of tobacco-specific nitrosamine adducts are at increased risk of developing lung cancer.
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PMID:DNA and hemoglobin adducts as markers of metabolic activation of tobacco-specific carcinogens. 156 1

The tumor suppressor gene APC was recently identified, and the cDNA was cloned from chromosome 5q21. Point mutations affecting APC are seen in the hereditary syndrome familial adenomatous polyposis, and point mutations in APC and a closely linked gene, MCC, as well as loss of heterozygosity involving chromosome 5q have been reported in sporadic colon cancer. To our knowledge, loss of heterozygosity involving APC or MCC or both has not yet been described in any other human cancer besides lung cancer. We used the polymerase chain reaction and DNA content flow cytometric nuclear sorting to examine 30 primary human esophageal cancers for loss of heterozygosity of APC or MCC or both. Loss of one allele was detected in 77% of 26 informative cases. These data suggest that loss of heterozygosity of regions on 5q including the APC and MCC genetic loci is involved in the development and/or progression of most human esophageal cancers. They imply that inactivation of APC, MCC, and/or a linked gene on chromosome 5q plays a role in the pathogenesis of some cancers of the upper gastrointestinal tract, as well as in colon cancer and familial adenomatous polyposis.
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PMID:Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers. 156 31

There have been a series of reports on the association of a genetic polymorphism at the cytochrome P450 CYP2D6 gene locus with cancer susceptibility. Many of these reports have remained contradictory either because of small numbers of patients studied or because of the limitations and controversy surrounding the pharmacokinetic assay used to identify affected individuals (poor metabolizers; PMs). We have recently developed a DNA-based assay that will allow the unequivocal identification of poor metabolizers and have applied this to the study of 1635 patients with different forms of cancer. Out of 361 lung cancer patients studied no statistically significant change in the proportion of PMs relative to controls was found. However, a significant increase in the proportion of poor metabolizers or heterozygotes was seen in leukaemia, bladder cancer and melanoma patients. This could be explained by a role for CYP2D6 in carcinogen detoxification or by linkage to another cancer-causing gene.
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PMID:Relationship between the debrisoquine hydroxylase polymorphism and cancer susceptibility. 160 Jun 8

Smokers of cigarettes are exposed to a number of carcinogens, including polycyclic aromatic hydrocarbons (PAHs), and are at a high risk for lung cancer. PAHs exert their carcinogenic activity after metabolic activation to reactive intermediates that can damage DNA through adduct formation. Measuring DNA adducts in peripheral white blood cells (WBC) could serve as a means of monitoring human exposure to genotoxic agents and subsequently risk assessment. In this study, DNA from WBC obtained from 39 lung cancer patients was examined for PAH-DNA adducts both in an ELISA using a polyclonal antibody against benzo[a]pyrene 7,8-diol-9,10-epoxide (BPDE)-DNA and the 32P-post-labeling technique. The ELISA results showed BPDE-DNA antigenicity in WBC DNA from 12/38 (32%) patients and adduct levels ranged from 1.5 to greater than 150 adducts in 10(8) nucleotides. The autoradiographs of chromatograms of 32P-post-labeled digests of WBC DNA from the 38 patients showed a variety of adduct spots; relative adduct labeling (RAL) values ranged from 0.3 to 407 adducts in 10(8) nucleotides. In 18 of the 38 (47%) persons an adduct spot was detected that co-chromatographed with the major BPDE-DNA adduct (BPDE-dG); RAL values ranged from 0.03 to 382 adducts in 10(8) nucleotides. Correlations were not significant between the adduct levels in WBC and smoking habits, age or sex. From 20 patients of the same group lung tissue was collected at surgery and examined for PAH-DNA adducts by ELISA and 32P-post-labeling assay. No significant correlation was found between DNA adduct levels in blood and lung. This finding stresses the limitations of the use of WBC as a surrogate for adduct levels in the target organ.
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PMID:Polycyclic aromatic hydrocarbon--DNA adducts in white blood cells from lung cancer patients: no correlation with adduct levels in lung. 160 Jun 21

The presence of antibodies to adult T cell leukemia (ATL) antigen: HTVL-I was studied in patients with chronic interstitial lung diseases such as diffuse panbronchiolitis (DPB) and idiopathic interstitial pneumonia (IIP). Anti-HTLV-I antibody was detected with a high frequency among these diseases (35% in DPB and 7% in IIP) compared with other diseases and healthy controls. We have termed the clinicopathological condition that includes these two disease categories of interstitial lung disease (DPB or IIP) and hematologic disorder (ATL associated with HTLV-I carrier state) HTLV-I associated bronchiolo-alveolar disorder (HABA). At the same time, HTLV-I related reaction (diffuse pattern for MT-1 and/or MT-2) was found except positive reaction of the antibody (granular pattern for MT-1) by immunofluorescent assay. The incidence of HTLV-I related reaction was high in interstitial lung diseases with a rate of 45% in DPB and 53% in IIP. Thus, the total frequency of presence of antibodies and related reactions was 80% in DPB and 60% in IIP. In lung cancer, the frequency was also high, although it was less than in DPB and IIP. We termed cases of anti-HTLV-I antibody positive lung cancer HTLV-I associated lung cancer (HALC). One typical patient with IIP who initially showed HTLV-I related reaction showed a positive antibody reaction 2 years later. Finally he presented with adenocarcinoma with effusion a further 2 years later. In order to examine HTLV-I proviral DNA integration, southern blotting by PCR was performed in patients with HTLV-I related reaction.2+ suggesting one of the causes of DPB.
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PMID:[HABA (HTLV-I associated bronchiolo-alveolar disorder)]. 163 42


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