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

Quantitative criteria of the action of chemical carcinogenic compounds serve as the basis for establishing the degree of danger they pose and of safety levels. The presence of the tumor is proposed as a specific index of the harmfulness of carcinogenic action. There are no indices for determining the initial stages of the neoplastic process before the tumor appears. Both the frequency and the time required for development are important. A study was made of the carcinogenic activity of benz(a)pyrene on rats. The drug was given by intratracneal administration in doses of .005, .02, .01, .05, and 2.5 mg repeated 10 times over a 10-month period. A total dose of .1 mg was minimally effective. However, .02 mg benz(a)pyrene was selected as the minimum effective single dose amount for estimated time periods longer than the life span of the animals and of the comparative span of human life. Tumors were produced in the lungs and other organs of the rats. Histological types varied. The dose given had an effect on the histological type of lung cancer. Large doses tended to produce epidermoid cancer while lower doses produced mostly adenocarcinoma. Some types found have not been recorded as spontaneously occurring in rats. The number of tumor-bearing animals diminished as the dose was reduced and the time for appearance of tumors increased. The number of spontaneous tumors in control animals increased with time. Animal strains with a high cancer susceptibility are needed in testing the small doses of a carcinogen since spontaneous tumors are an indication of sensitivity to carcinogenic substances. However, random-bred animals have a closer approximation to the human population and may be better for some experiments. For the optimal experiment, administration of a carcinogen should be over the entire life span of the individual. Another procedure is by using different doses in a short-term experiment to obtain a dose-time effect. On the basis of data obtained, the maximum permissible concentration of benz(a)pyrene in the ambient air can be determined.
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PMID:Predicting the risk of tumor occurrence under the effect of small doses of carcinogens. 126 13

Epidemiological studies suggested a protective effect of certain phenotypes of polymorphic foreign-compound-metabolizing enzymes in some types of cancer. Poor metabolizers (PM) of debrisoquine 4-hydroxylase (cytochrome P-450IID6, CYP2D6) were found to be underrepresented among patients with lung cancer. Recent advances in molecular genetic characterization of CYP2D6, glutathione S-transferase (GST) class Mu, and arylamine N-acetyltransferase enabled genotypical determination of mutant alleles in lung cancer patients. Restriction fragment length polymorphism (RFLP) with a cDNA gene probe of CYP2D6 was analyzed in 79 lung cancer patients who were phenotyped with debrisoquine. Mutant alleles were detected by allele-specific polymerase chain reaction (PCR). In the same individuals, genotype of GST class Mu was analyzed by PCR and correlated with ex vivo activity of glutathione conjugation towards trans-stilbene oxide. RFLP patterns allowed discrimination between the slow and fast genotype of N-acetyltransferase as well as the heterozygotes. Three phenotypical PMs of debrisoquine (3.8%) were confirmed by PCR and RFLP. No PM could be unambiguously recognized only by RFLP patterns. The PMs were characterized by PCR and RFLP as carriers of the 29B/29B (n = 1), 29A/29B (n = 1), and 29A/44 (n = 1) mutant alleles. Higher debrisoquine hydroxylase activities were found in the homozygous EMs, who possess two active genes, as compared to heterozygous EMs, who have only one active gene. The patients with phenotypically impaired GST Mu activity were confirmed as such by PCR. A complete correspondence between phenotyping of N-acetyltransferase (with caffeine) and genotyping was found. The new genetic techniques proved to be powerful tools for molecular-epidemiological studies aimed at establishing host factors of cancer susceptibility.
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PMID:Mutant genes of cytochrome P-450IID6, glutathione S-transferase class Mu, and arylamine N-acetyltransferase in lung cancer patients. 135 78

The cytochrome P450-dependent monooxygenases play a central role in the metabolism of chemical carcinogens. The action of these enzymes can lead to either carcinogen detoxication or activation. Differences in P450 expression in animal models give rise to large differences in susceptibility to chemical carcinogens, so genetic polymorphisms in P450 expression may be expected to be an important factor in individual human susceptibility to cancer. Of particular interest is the genetic polymorphism at the cytochrome P450-debrisoquine/sparteine hydroxylase locus (CYP2D6). Although this is a minor liver P450, its polymorphic expression is associated with the abnormal metabolism of at least 30 therapeutic drugs, including beta-blockers and tricyclic antidepressants. Conflicting reports have been made on the association of this polymorphism with cancer susceptibility. This disagreement may be attributable to limitations of the phenotyping assay used to identify affected individuals (poor metabolizers, PMs). In order to clarify these anomalies, we have developed a simple DNA-based assay with which we can identify the majority of PMs. The assay is centered around the primary gene defect responsible for the polymorphism, a G to A transition at the junction of intron 3/exon 4 which results in a frame-shift in the resultant mRNA. The frequency of this mutation is 70-80% in PMs. We have studied the frequency of mutated alleles in a control population and in a wide range of cancer patients. No association between this polymorphism and lung cancer susceptibility was observed; however, in other populations of cancer patients some very interesting shifts were found in the proportion of PMs and heterozygotes from that in the normal population.
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PMID:Molecular genetic analysis of the cytochrome P450-debrisoquine hydroxylase locus and association with cancer susceptibility. 148 38

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

The glutathione transferase mu gene (GST1) and the debrisoquine hydroxylase gene (CYP2D6) are known to be polymorphic in the human population and have been associated with increased susceptibility to cancer. Smokers with low lymphocyte GST mu activity are at higher risk for lung cancer, while low debrisoquine hydroxylase activity has been correlated with lower risk for lung and bladder cancer. Phenotypic characterization of these polymorphisms by lymphocyte enzyme activity (GST) and urine metabolite ratios (debrisoquine) is cumbersome for population studies. Recent cloning and sequencing of the mutant alleles of these genes has allowed genotyping via the polymerase chain reaction (PCR). Advantages of PCR approaches are speed, technical simplicity, and minimal sample requirements. This article reviews the PCR-based methods for detection of genetic polymorphisms in human cancer susceptibility genes.
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PMID:Detection of DNA sequence polymorphisms in carcinogen metabolism genes by polymerase chain reaction. 168 53

Examples of practical approaches to molecular epidemiology of human cancer are described. Biomarkers of carcinogen exposure or inherited host factors for cancer susceptibility are discussed. Major advances have been made in the detection of carcinogenmacromolecular adducts through the use of high performance liquid chromatography, immunoaffinity chromatography, the 32P-postlabeling assay, enzyme immunoassays, gas chromatography/mass spectroscopy and synchronous spectrophotofluorimetry. The polycyclic aromatic hydrocarbon-DNA adducts are the most extensively studied in this field and together with antibodies to these adducts found in human serum, they have become useful indicators of exposure to carcinogens. Assays for various kinds of alkyl-DNA adducts have also been developed and the presence of these adducts have been documented in human tissues. Carcinogen-protein adducts have proven to be useful molecular dosimeters of carcinogen exposure. For example, 4-aminobiphenyl hemoglobin adducts are highly correlated with exposure to tobacco smoke. The study of the molecular aspects of interindividual differences in the metabolism and activation of xenobiotics and other genetic markers [DNA-restriction fragment length polymorphisms (RFLPs), mutations, and functional loss of specific genes in carcinogenesis] is an emerging new field that is discussed in the context of genetic susceptibility to cancer. The cytochrome P450 phenotypes and acetylation phenotype are examples of genetic markers that indicate an individual's potential for metabolism of exogenous substances. Further, inherited genetic polymorphic markers, e.g., DNA-RFLPs at protooncogene loci (HRAS-1 and L-myc) have been examined in a case-control study of lung cancer. Data concerning mutations of protooncogenes (H-, K-, and N-RAS) and tumor suppressor genes (retinoblastoma and p53 genes) in various common cancers are providing evidence of multiple genetic lesions that occur during the multistage process of carcinogenesis.
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PMID:Biochemical and molecular epidemiology of cancer. 191 Jun 3

The identification of genetic traits that predispose individuals to environmentally induced cancers is one of the most important problems in cancer risk assessment. Genetic deficiency in the mu-isozyme of the glutathione (GSH) S-transferases (EC 2.5.1.18) has recently been associated with increased lung cancer risk. To test whether this association could arise from a metabolically mediated sensitivity to mutagenic substrates, cytogenetic damage in lymphocytes from 21 isozyme-deficient and 24 nondeficient individuals was induced. Cells were treated with trans-stilbene oxide, an excellent substrate for GSH S-transferase mu, or cis-stilbene oxide, a poor substrate for the isozyme. Sister chromatid exchange induction was measured as an indicator of cytogenetic damage. A trimodal distribution of trans-stilbene oxide-induced sister chromatid exchanges was observed in the population, including resistant, moderate, and highly sensitive groups. Glutathione S-transferase mu deficiency was associated with both moderate and high sensitivity to trans-stilbene oxide-induced damage but had no effect on cis-stilbene oxide-induced sister chromatid exchange. The results indicate that GSH S-transferase mu, a proposed marker of cancer susceptibility, is also a marker of susceptibility to the induction of cytogenetic damage by a certain class of mutagens. The differential effects of the cis- and trans-isomers of stilbene oxide illustrate that the stereoselectivity of GSH S-transferase mu toward various alkene epoxide substrates can be an important factor affecting individual sensitivity to DNA-damaging epoxides.
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PMID:Human glutathione S-transferase deficiency as a marker of susceptibility to epoxide-induced cytogenetic damage. 230 18

All the 57 female lung cancer patients in Xu-Hui District, Shanghai discovered during 1985 were used as subjects of this study, each was matched with 2 of her near neighbours of same sex and within 5 years of age difference. Smoking, chronic bronchitis, pulmonary tuberculosis and family history of tumour were found to be related with lung cancer in single variable analysis. Upon stratification, smoking and pulmonary tuberculosis were still found related to lung cancer and considered as risk factors with OR and its 95% confidence interval 6.996, 3.23-15.14 and 4.82, 1.37-19.97 respectively. But chronic bronchitis failed to relate with lung cancer and was considered as a confounding factor. Of all the female lung cancer cases only 49.1% and 19.3% were smokers and TB patients respectively, hence smoking and TB could be responsible only for a small portion. In cancer cytology, squamous-cell carcinoma appeared to show association with smoking while adenocarcinoma did not. Among female lung cancer cases the proportion of adenocarcinoma exceeded that of squamous-cell carcinoma, and appeared unrelated with smoking. More family members of the lung cancer cases seem to have had malignant histories, suggesting that a hereditary factor of cancer susceptibility might be involved.
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PMID:[A case-control study of female lung cancer at XuHui district in Shanghai]. 273 51

An association between the BstU I 1-1 (Pro-Pro) genotype of the p53 codon 72 polymorphism and lung cancer has previously been reported by Kawajiri et al. A reanalysis of the data by Kawajiri et al. revealed no significant difference between patients and controls with respect to allele frequencies, and the increased frequency of BstU I 1-1 homozygotes was mostly ascribable to a deviation from the Hardy-Weinberg equilibrium. In an attempt to replicate the results by Kawajiri et al. we have studied three p53 polymorphisms (BstU I and Msp I RFLPs in exon 4 and intron 6 respectively and a 16 bp duplication in intron 3) and their haplotypes in Swedish lung cancer patients and controls. The results concerning the codon 72 polymorphism were largely negative. Thus there was no significant association between lung cancer and the BstU I 1-1 type, and only a marginal difference (P = 0.044) with respect to the BstU I allele frequency when lung cancer patients were compared with patients with chronic obstructive pulmonary disease (COPD). However, when the analysis was based on haplotype frequencies larger differences appeared and it was found that only BstU I 1 (pro) alleles linked to 16 bp 1 alleles were associated with lung cancer. Pro alleles linked to the 16 bp duplication appeared instead to confer some protection against cancer. Thus the codon 72 alleles need not be functionally involved in lung cancer, but may rather be markers in linkage disequilibrium with other cancer susceptibility sites on p53.
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PMID:P53 polymorphisms and haplotypes in lung cancer. 755 81

Prevention is an important and effective measure for reducing death caused by cancer. Thus information on individual susceptibility to cancer is valuable in suggesting high risk individuals to avoid intake of carcinogenic substances and receive frequent physical screening. To this end, polymorphisms found within cytochrome P450 (CYP) genes implicated in the metabolism of procarcinogens are expected to be good genetic targets in assessing human cancer susceptibility. We have found polymorphisms in the CYP2E1 and CYP1A1 genes associated with lung cancer susceptibility, though there were some discrepancies from observations made by other investigators. Discrepancies among investigators from different regions, however, are very common in these pharmacogenetic studies. We present an explanation for these discrepancies, difficulties associated with prediction of relative risk of individuals, and future directions.
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PMID:Assessment of cancer susceptibility in humans by use of genetic polymorphisms in carcinogen metabolism. 758 87


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