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Biomedical subjects

S Anttila

Publications and source records attributed to S Anttila.

At least 55 records · Page 3Linked to original sources
PubMed1995

p53 antibodies in the sera of lung cancer patients: comparison with p53 mutation in the tumour tissue.

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.

Autoantibodies↗
PubMed1995

Diagnosis of polymorphisms in carcinogen-activating and inactivating enzymes and cancer susceptibility--a review.

Up to 90% of all cancers are possibly caused by environmental factors, such as tobacco smoke, diet and occupational exposures. The majority of chemical carcinogens require metabolic activation before they interact with cellular macromolecules and can cause cancer initiation. The xenobiotic-metabolising machinery contains two main types of enzymes: the phase-I cytochromes P-450 (CYP) mediating oxidative metabolism, and phase-II conjugating enzymes. Several phase-I and phase-II genes have recently been cloned and identified in humans. Many of them show polymorphism and have been suggested to contribute to individual cancer susceptibility as genetic modifiers of cancer risk. Altered phenotypes and genotypes in the CYP subfamilies CYP1A1, CYP2D6 and CYP2E1 have been associated with tobacco smoke-induced lung cancer and other cancers. Defective glutathione S-transferase (GST) and N-acetyltransferase (NAT) enzymes have been associated with an increased risk of developing lung and bladder cancer. There are also several studies in each category in which no associations have been found. The risk of developing lung cancer is dramatically (up to 40-fold) elevated in subpopulations having simultaneously high-risk genotypes in CYP1A1 and GSTM1. There are several difficulties in this area of research. First, many of the observed restriction-fragment length polymorphisms (RFLPs) are due to mutations in introns or other silent areas of DNA, raising the possibility that any associations found between RFLPs and cancer occur only by chance. Second, biologically plausible mechanisms linking genotypes and cancer are lacking in most of the observed cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Arylamine N-Acetyltransferase↗
PubMed1995

Detection of loss of heterozygosity in the p53 tumor suppressor gene using a PCR-based assay.

Inactivation of the p53 tumor suppressor gene has been reported to be a prognostic factor in several human cancer types. Normal function of the gene is affected by deletion in one allele; dysfunction of the other allele is often caused by a mutation. In tumors of heterozygous individuals, deletion of one allele can be detected as loss of heterozygosity (LOH). A recently found variable number of tandem repeats (VNTR) segment in intron 1 of the p53 gene seems to be highly polymorphic and, therefore, a very useful marker in detecting LOH in various types of tumor samples. We in vitro amplified the VNTR segment from genomic DNA samples of 101 lung cancer patients and run conventional agarose gel electrophoreses in order to detect the alleles of various length, differing by the number of repeats. The usefulness of the method was studied using DNA from white blood cell samples and from fresh and formalin-fixed, paraffin-embedded tumor samples. Of the patients, 56% were found to have two different alleles, i.e. were informative in this assay. In 18% of the lung tumors from the informative cases, LOH in the p53 suppressor gene was detected.

Adenocarcinoma↗
PubMed1995

Expression and polymorphism of glutathione S-transferase in human lungs: risk factors in smoking-related lung cancer.

The relationships between smoking and the expression of glutathione S-transferase (GST*) isozymes GSTM1-1, GSTM3-3, GSTP1-1 and GSTA1-1/2-2 (GSTA1/2), or between smoking and activities of epoxide hydrolase (EH) and aryl hydrocarbon hydroxylase (AHH) were investigated in lung samples from 27 patients with lung cancer and 11 control patients by immunoblot analysis and enzyme assays. Determination of genotypes in blood leucocyte DNA showed that possession of the mu-class GSTM1 gene was closely related to the expression of GSTM1-1 and GSTM3-3 enzymes in lung cytosol: patients with the GSTM1 null genotype had no detectable GSTM1 protein and less GSTM3 protein than patients with the GSTM1 gene (P < 0.001). Absence of the GSTM1 gene did not affect the content of phi-class GSTP1-1 or alpha-class GSTA1/2. GST activity towards 1-chloro-2,4-dinitrobenzene was lower (P < 0.01) in patients lacking the GSTM1 gene than in those expressing GSTM1; in general, patients with a low GSTM3-3, GSTP1-1 or GSTA1/2 content also had significantly less overall GST activity. The pulmonary content of GSTP1-1 was greater in cancer than in non-cancer patients (P < 0.05). Smoking did not influence the levels of GST isozymes or the EH activity. In contrast, the AHH activity was significantly (P < 0.01) increased by smoking. Neither AHH nor EH showed a correlation with GSTM1 polymorphism. Our data support the idea that in smokers who lack the GSTM1 gene, activation of carcinogens in tobacco smoke (e.g. benzo[alpha]pyrene) is increased, while the efficacy of detoxification is limited both qualitatively (absence of GSTM1-1 enzyme and low expression of GSTM3-3 enzyme) and quantitatively (low overall GST activity). This imbalance in the metabolism of carcinogens may explain the increased susceptibility to lung cancer reported in smokers with the GSTM1 null genotype.

Animals↗
PubMed1995

Metabolic polymorphism affecting DNA binding and excretion of carcinogens in humans.

A case-control study on lung cancer patients demonstrated the pronounced effect of tobacco smoke on pulmonary carcinogen metabolism and suggested the existence of a metabolic phenotype at higher risk for tobacco-associated lung cancer. Lung cancer patients who were recent smokers showed in their lungs (i) significantly induced CYP1A1-related enzyme activity vs smoking non-lung cancer patients; (ii) increased benzo(a)pyrene (BP) tetrol formation from BP 7,8-diol by lung microsomes; and (iii) high levels of cytochrome P4501a1 by immunohistochemical staining. Levels of bulky aromatic DNA adducts (by 32P-postlabelling) and of BP-diol-epoxide (BPDE) adducts (by HPC/fluorometry) were quantified in lung parenchyma. Aryl hydrocarbon hydroxylase activity and the level of BPDE-DNA adducts (r = 0.91; p < 0.001) and to a lesser degree bulky DNA adducts were correlated. Thus pulmonary CYP1A1 expression (inducibility) controls in part polycyclic aromatic hydrocarbon-DNA adduct formation in tobacco smokers and, therefore, appears to be associated with lung cancer risk. High risk subjects for lung cancer among smokers may be identifiable through genotyping for polymorphic drug metabolizing enzymes in combination with molecular dosimetry of carcinogen-DNA adducts and mutation analysis in target (surrogate) cells. Such studies in a Finnish cohort of lung cancer patients and controls are in progress. Interim results of the effect of metabolic polymorphism on the level of PAH-DNA adducts and on the excretion of mutagens in urine are summarized.

Biotransformation↗
PubMed1995

p53 and ras gene mutations in lung cancer: implications for smoking and occupational exposures.

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.

Genes, p53↗
PubMed1994

Asbestos bodies in bronchoalveolar lavage fluid in relation to occupational history.

Concentrations of asbestos bodies (AB) were assessed by optical microscopy of 10 ml iron-stained samples and compared with the exposure history acquired by personal interview for 156 patients. Concentrations equalling or exceeding 1 AB/ml were found in 85% of patients who had been heavily exposed to asbestos and only 7% of those who were unlikely to have been exposed. Elevated AB concentrations were observed among primary asbestos, shipyard and construction workers. Smoking was not found to affect the AB concentrations. The use of Papanicolaou-stained cytological Millipore preparations during routine screening was a less sensitive method for the assessment of AB concentrations than that involving iron-stained preparations. The expression of AB concentration as AB/ml or AB/million cells were found to be equally useful indicators of exposure. The correlation between AB concentration and exposure history was greater than in earlier studies on workers exposed to chrysotile. Concentrations exceeding 1 AB/ml were indicative of a nontrivial exposure to asbestos. Despite the observed correlation between AB concentration and exposure history, the individual variability of AB counts, methodological differences and laboratory-bound reference values are important in the interpretation of AB concentrations in bronchoalveolar lavage (BAL) fluid at individual level.

Adult↗
PubMed1994

Combined effect of CYP1A1 inducibility and GSTM1 polymorphism on histological type of lung cancer.

The combinations of the CYP1A1 inducibility and GSTM1 polymorphism have been investigated in relation to the histological type and peripheral or bronchial location of lung cancer in 54 surgically treated, current smoker lung cancer patients. The induced CYP1A1 was detected in 46 patients (85%) and the homozygous GSTM1 null genotype in 32 patients (59%). The role of CYP1A1 inducibility was found to be more important than that of GSTM1 polymorphism, because the non-inducible CYP1A1 was associated solely with bronchial tumours (P = 0.001), mainly squamous cell carcinomas. In patients with inducible CYP1A1, the expressing GSTM1 gene appeared to have a protective effect against contracting bronchial lung cancer, since 88% (14/16) of the lung tumours in this patient group were peripheral, whereas almost equal numbers of peripheral and bronchial tumours were observed in those patients lacking the gene (P = 0.037).

Aryl Hydrocarbon Hydroxylases↗
PubMed1994

Detection of serum p53 protein in lung cancer patients.

Serum levels of p53 protein were examined in 23 cases of lung cancer (many with potential asbestos exposure), 23 unexposed matched hospital control subjects, 58 unmatched general population control subjects, and 4 people with nonmalignant lung disease using an enzyme-linked immunosorbent assay and Western immunoblotting. Average levels of serum p53 in the lung cancer patients (0.55 ng/mL) were higher than in the cases of nonmalignant lung disease (0.42 ng/mL) or in the matched (0.32 ng/mL) or unmatched (0.31 ng/mL) control subjects, but the differences were not statistically significant. However, three of the cases of lung cancer (13%) were found to have serum p53 levels much greater than those of the control subjects (> 2 SD above the mean) and to have confirmatory positive Western blots for p53. The tumors from these subjects demonstrated increased levels of p53 in the tissue by immunohistochemistry and/or the presence of mutations in the p53 gene. These results suggest that p53 protein can be detected in serum in a portion of lung cancer cases with p53 alterations in the tumor tissue.

Aged↗
PubMed1994

Asbestos exposure and the risk of lung cancer in a general urban population.

OBJECTIVES: The aim of the study was to investigate the asbestos-associated risk of lung cancer according to histological type of cancer, lobe of origin, pulmonary concentration, and type of amphibole fibers and also to estimate the etiologic fraction of asbestos for lung cancer. METHODS: The pulmonary concentration of asbestos fibers in 113 surgically treated male lung cancer patients and 297 autopsy cases among men serving as referents was determined by scanning electron microscopy. The age- and smoking-adjusted odds ratios of lung cancer were calculated according to pulmonary fiber concentration for all lung cancer types, squamous-cell carcinoma, and adenocarcinoma and for the lower-lobe and the upper- and middle-lobe cancers. RESULTS: The risk of lung cancer was increased according to the pulmonary concentration of asbestos fibers (f) of 1.0 to 4.99 x 10(6) f.g-1 [odds ratio (OR) 1.7] and > or = 5.0 x 10(6) f.g-1 (OR 5.3). The odds ratios associated with fiber concentrations of > or = 1.0 x 10(6) f.g-1 were higher for adenocarcinoma (OR 4.0) than for squamous-cell carcinoma (OR 1.6). The asbestos-associated risk was higher for lower lobe tumors than for upper lobe tumors. The risk estimates for anthophyllite and crocidolite-amosite fibers were similar, except for the risk of squamous-cell carcinoma. An etiologic fraction of 19% was calculated for asbestos among male surgical lung cancer patients in the greater Helsinki area. CONCLUSIONS: Past exposure to asbestos is a significant factor in the etiology of lung cancer in southern Finland. The asbestos-associated risk seems to be higher for pulmonary adenocarcinoma and lower-lobe tumors than for squamous-cell carcinoma and upper-lobe tumors.

Adult↗
PubMed1993

Immunohistochemical localization of glutathione S-transferases in human lung.

Glutathione S-transferases (GST) detoxify a number of carcinogenic electrophiles including diol-epoxide metabolites of polycyclic aromatic hydrocarbons. The distribution of GSTs A1/A2, M1, M2, M3, and P1 has been studied in lung tissue from 32 subjects by immunohistochemistry using rabbit polyclonal antibodies. GSTA1/A2 and GSTP1 were found to be the most abundant GSTs in human lung, being present in the bronchial and bronchiolar epithelium of all individuals studied. The staining intensity for GSTA1/A2 varied more than that for GSTP1 between individuals. GSTM1, a polymorphic mu-class enzyme, was ambiguously detected in lung tissue and, if expressed, is present at very low levels. GSTM2, a striated muscle-specific isozyme, occurred minimally in the epithelium of the terminal airways, and GSTM3, an enzyme of broad extrahepatic occurrence, was observable in the ciliated airway epithelium and smooth muscle of the lung. The staining for GSTM3 varied from minimal to very intense between individuals; in the bronchial epithelium, it was more abundant in current smokers than in exsmokers. The immunostaining for GSTs in general was most intense in the bronchial epithelium decreasing in the distal airways, in contrast to the previously described peripheral localization of the polycyclic aromatic hydrocarbons activating the P450IA1 enzyme. The localization of GSTs in the bronchial wall suggests that GST polymorphisms may contribute to susceptibility, especially to bronchial tumors of tobacco smokers.

Adult↗
PubMed1993

K-ras mutations in human adenocarcinoma of the lung: association with smoking and occupational exposure to asbestos.

We investigated point mutational activation of the ras genes (K-ras codons 12, 13 and 61; N-ras codons 12, 13 and 61; H-ras codons 12 and 61) in primary, resected lung cancer by dot blotting and oligonucleotide hybridization. K-ras mutations were found in 14 (29%) of the 48 lung tumour specimens examined, but no N-ras or H-ras mutations were found. The highest frequency of K-ras mutation was observed in adenocarcinoma: 12 of the 21 samples studied (57%) had a mutation, which is one of the highest frequencies reported for lung adenocarcinoma. The commonest type of mutation in these lung tumour samples consisted of transversions: we observed 11, of which 8 (57% of all mutations) were G to T transversions. Most of the 48 patients studied had a history of heavy smoking, either with or without evidence of occupational exposure to asbestos. Statistical analysis revealed--in addition to the highly significant association between the adenocarcinoma type of lung cancer and K-ras mutation--a clear association of K-ras mutations with heavy life-time smoking (> or = 50 pack-years of cigarette smoking; odds ratio (OR) 4.9, 90% CI 1.2-19.5, multivariate analysis). In addition, occupational asbestos exposure showed an elevated, but non-significant, OR of 2.2 (90% CI 0.6-8.7) with the presence of K-ras mutation. We conclude that the occurrence of K-ras mutations in adenocarcinoma of the lung is frequent, and that such mutations are associated with heavy life-time exposure to tobacco smoke, possibly in combination with occupational exposure to asbestos fibres.

Adenocarcinoma↗
PubMed1993

Asbestos exposure among Finnish lung cancer patients: occupational history and fiber concentration in lung tissue.

In a series of 65 surgically treated lung cancer patients, past exposure to asbestos was evaluated by personal interviews, and by scanning electron microscopy analyses of the mineral fibers in lung tissue. Lung tissue samples of 17 autopsied male office workers were analyzed as referents. According to occupational history, 37% of the lung cancer patients had definite or probable, 31% possible, and 32% unlikely exposure to asbestos. The fiber concentration in the lung tissue ranged from < 0.1 to 65 million fibers per gram dry tissue in the lung cancer group, and from < 0.1 to 0.8 million fibers per gram dry tissue in the reference group. In 26% of the lung cancer patients, but in none of the referents, the fiber concentration exceeded 1 million fibers per gram dry tissue. Most of the exposed patients had been employed in various construction jobs, and valuable information about the exposure levels could be obtained by the mineral fiber analyses. In general, there was a good accord between the exposure categorization and the fiber burden measured in the lung.

Adenocarcinoma↗
PubMed1993

The human CYP2E1 gene and lung cancer: DraI and RsaI restriction fragment length polymorphisms in a Finnish study population.

We investigated point mutational DraI and RsaI restriction fragment length polymorphisms (RFLPs) in the CYP2E1 gene in 101 lung cancer patients, 40 patients with other pulmonary diseases and 121 healthy control subjects. In the DraI RFLP analysis of the 121 healthy control subjects, 96 had the DD genotype, 24 the CD genotype and one the CC genotype. Genotypic distribution in the patients with other pulmonary disease showed a similar trend (P = 0.50), though the group was considerably smaller. The distribution of DraI genotypes in the lung cancer patients was not significantly different from that of the healthy controls (P = 0.44). We were not able to reproduce the results of a Japanese report describing a statistically significant association between the rare DraI RFLP genotype CC and predisposition to lung cancer. Furthermore, this genotype was much less frequent in our study populations than in the Japanese study. The other point mutation studied, which results in RsaI restriction site polymorphism in the 5'-flanking region of the CYP2E1 gene, was almost absent in our study groups. These findings on our Finnish lung cancer population suggest that the CYP2E1 gene polymorphisms studied do not have an important role in susceptibility to lung cancer.

Base Sequence↗
PubMed1993

The GSTM1 null genotype as a potential risk modifier for squamous cell carcinoma of the lung.

The identification of genetic traits that predispose individuals to environmentally induced cancers is one of the challenges in the assessment of individual cancer risk. For this reason, individual variations in the expression of enzymes involved in biotransformation reactions have been extensively studied. One such polymorphic enzyme is GSTM1, which belongs to the class Mu of glutathione S-transferases (GSTs), and is only expressed in 55-60% of Caucasians. Previous data suggest that smokers lacking GSTM1 activity may be at greater risk of developing lung cancer. In this study, we used a polymerase chain reaction-based method to examine this issue in a Finnish study population. We found that 44% of a control group of 142 individuals lacked the GSTM1 gene, i.e. they had the GSTM1 null genotype; the rest were either homozygous or heterozygous for the expressed GSTM1 alleles. In a group of 36 patients with non-neoplastic pulmonary diseases, an identical distribution was observed. However, among 138 lung cancer patients the distribution of the GSTM1 genotypes deviated from that found in the healthy controls (53% nulled; odds ratio 1.5, 95% confidence interval 0.9-2.3). Furthermore, when the lung cancer patients were analysed by tumour type, a statistically significant increase in the GSTM1 null genotypes (62%; n = 71) was seen in the squamous cell carcinoma group, with an odds ratio of 2.1 (95% confidence interval 1.2-3.8). These data support the suggestion that GSTM1 null genotype may act as a risk modifier in lung cancer.

Base Sequence↗
PubMed1993

PCR-based CYP2D6 genotyping for Finnish lung cancer patients.

Polymorphism of the gene encoding for debrisoquine hydroxylase, i.e. CYP2D6, was determined genotypically for 122 healthy controls and 106 lung cancer patients using Xba I restriction fragment length polymorphism (RFLP) analysis, together with a combination of two recently published polymerase chain reaction (PCR) based approaches. Three different mutated alleles of the CYP2D6 gene were detected; CYP2D6B comprised 11.1% and 10.4% of the total alleles in the controls and in the lung cancer patients, CYP2D6A had frequencies of 5.7% and 2.8%, and CYP2D6D had frequencies of 3.3% and 2.4%, respectively. Only 17 of the 24 44 kb Xba I alleles (71%) were confirmed as defective alleles carrying the mutation in CYP2D6B loci, whereas all four 15 + 9 kb Xba I alleles contained the CYP2D6B mutation. Out of the 122 healthy controls, seven subjects (5.7%) were detected as poor metabolizers (PMs) of debrisoquine by the presence of two defective alleles, whereas only one PM genotype was found in the lung cancer patient group (0.9%). The reliability of this analysis was confirmed in a subgroup of the control subjects phenotyped by debrisoquine, where a perfect correlation between CYP2D6 phenotype and genotype was obtained. We observed no significant difference in the allelic frequencies between lung cancer patients with a history of heavy smoking and those who smoked less. However, statistical analysis showed a significant difference (p = 0.05) in distribution of the PM-associated genotypes between lung cancer patients (1/106) and healthy controls (7/122). This data thus supports the hypothesis that there is an increased risk of lung cancer for individuals who are extensive metabolizers of debrisoquine.

Aged↗
PubMed1993

Lung cancer in the lower lobe is associated with pulmonary asbestos fiber count and fiber size.

We studied exposure to asbestos, pulmonary fibrosis, fiber count, and fiber size in relation to the lobar origin of lung cancer in 90 consecutive patients. Among the 32 patients with a history of occupational exposure to asbestos, 22 were construction workers. The proportion of lower-lobe tumors increased with the duration of exposure from 45% in those working less than 15 years to 82% in those working 15 years or more in the construction trade, as compared with 25% in patients who were probably not exposed. The location of the tumor in the lower lobe was explained by the high number of total fibers [odds ratio (OR) = 9.0, CI = 2.3-34.6), of fibers 3 microns and longer (OR = 22.1, CI = 3.9-125), and fibers of anthophyllite (OR = 14.6, CI = 2.4-83.4) and crocidolite (OR = 7.0, CI = 1.2-41.2) when the effect of smoking and fibrosis was adjusted in the logistic regression analysis. The location of the tumor did not correlate with fibrosis, pack-years smoked, or the number of short (< 3 microns) fibers. Our findings suggest that asbestos causes an excess of lower-lobe tumors at a relatively low exposure level, independently of pulmonary fibrosis.

Asbestos↗