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H Vainio

Publications and source records attributed to H Vainio.

At least 145 records · Page 8Linked to original sources
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

Cancer etiology: agents causally associated with human cancer.

Cancer is a multifactorial and multistage process, the exact mechanisms of which are still only partially known. However, even in the absence of a complete understanding of the process of carcinogenesis, we have been able to identify several factors which modify the risk of tumour development in humans. These include both endogenous and environmental factors, ranging from exposure to a single identified chemical to the occupations we follow in order to make our living. Cancer prevention strategies may differ in different parts of the world. In Europe, lung cancer is responsible for about one fourth of all cancer deaths and most of it could be prevented by eliminating tobacco smoking. Other exposures that can be controlled include occupational exposures to agents known to cause cancer at sites such as lung, bladder, paranasal sinuses, leukaemia, lymphoma and liver, as well as exposure to sunlight, known to be associated with both non-melanocytic and melanocytic skin cancer. Liver cancer is a common cancer in other regions of the world where hepatitis B virus (HBV) infection is endemic; in these areas, fungal contamination of food is also common. While immunization against HBV may be the method of choice in the long run, reduction of exposure to aflatoxins might be a more useful intermediate goal in primary prevention because of the strong interaction between hepatitis B and aflatoxin exposure on liver cancer risk. To date, few chemical agents have been proved to be of etiological relevance to cancer in humans at sites such as the breast (with the exception of oestrogenic hormones), ovary, colon-rectum and prostate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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↗
PubMed1993

Polymorphism in CYP1A1 and CYP2D6 genes: possible association with susceptibility to lung cancer.

Polymorphism of CYP2D6 gene encoding for debrisoquine hydroxylase was determined genotypically for 94 controls and 77 lung cancer patients using a polymerase chain reaction-based application. Both of the point mutations that give rise to deficient alleles of the CYP2D6 gene are detectable by this method. Out of the 94 healthy controls, 3 individuals (3.2%) had poor metabolizer (PM) genotypes, whereas no PM genotypes were detected in the lung cancer patient group. We observed no difference in the allelic frequencies for either homozygous extensive metabolizers (EMs) or heterozygous EMs between the lung cancer patients and the healthy controls. However, the absence of the poor metabolizer genotype (0/77) in the lung cancer patients is compatible with the hypothesis that there is an increased risk of lung cancer for individuals who are extensive metabolizers of debrisoquine. Another member of the cytochrome P450 gene superfamily that has attracted interest for its potential role in human pulmonary carcinogenesis is the CYP1A1 gene. In CYP1A1 gene studies, a polymorphic site assessable to MspI gives rise to two different hybridizable fragments in a Southern blot analysis (alleles C1 and C2, respectively). The C2C2 genotype has previously been associated with an increased risk of lung cancer. So far 74 lung cancer patients, 30 patients with lung diseases other than cancer, and 118 healthy controls have been studied for CYP1A1 gene polymorphism. No association between the MspI restriction fragment length polymorphism in the CYP1A1 gene and lung cancer susceptibility has been found.

Alleles↗
PubMed1993

Interaction between smoking and asbestos in human lung adenocarcinoma: role of K-ras mutations.

To investigate the role of tobacco smoking and asbestos fibers in the etiology of human lung cancer, we examined the activating point mutations in the K-ras oncogene in DNA samples from 49 patients. Mutations were found more often in tissue from adenocarcinomas (12/21) than in tissue from tumors other than nonadenocarcinomas of the lung (3/28). Among the adenocarcinoma patients, asbestos exposure was predictive of K-ras mutation (odds ratio, 4.9; 95% confidence interval, 0.7-34.3); in patients with other types of lung cancer, the relation appeared to be an inverse one, but the numbers were small. The proportion of heavy smokers (over 50 pack-years) was 60% among people with K-ras mutations and 35% among the K-ras-negative subjects, suggesting that smoking causes K-ras mutations. If mutations in K-ras genes are caused by smoking, asbestos would act as a promoting agent by conferring selective growth conditions for clonal expansion on these mutated cells. Asbestos may favor recruitment of (initiated) K-ras mutation-positive cells in the multistage process of carcinogenesis by stimulating cellular growth.

Adenocarcinoma↗
PubMed1993

Lobe of origin of lung cancer among asbestos-exposed patients with or without diffuse interstitial fibrosis.

The effect of asbestos exposure and asbestos-associated fibrosis on the lobe of origin of lung cancer was studied among 108 lung cancer patients. The asbestos-exposed patients had significantly more lower lobe tumors than the unexposed patients. Similar results were obtained when occupational history or lung fiber concentration was used as an indicator of past occupational exposure to asbestos. The predominance of lower lobe tumors occurred even among exposed patients with no histological signs of asbestosis in their lung specimens. Both bronchial and peripheral cancers showed a lower lobe predominance among the exposed patients. Smoking history did not affect the lobar distribution of the tumors. No significant differences occurred for the histological cell types of the tumors between the exposed and unexposed patients. Patients with asbestosis had, however, more adenocarcinomas than the unexposed patients. The results indicate that asbestos may increase the risk of lung cancer even in the absence of asbestosis.

Adult↗
PubMed1993

Carcinogenicity of mercury and mercury compounds.

Mercury and mercury compounds are widely used in modern society, but only sparse data are available on their carcinogenicity. Methylmercury chloride causes kidney tumors in male mice. Mercury chloride has shown some carcinogenic activity in male rats, but the evidence for female rats and male mice is equivocal. Other mercury compounds and metallic mercury have not been tested adequately in experimental animals. Epidemiologic data are available for chloralkali workers, dentists and dental nurses, and nuclear weapons workers, three groups occupationally exposed to low levels of mercury and its compounds, but those highly exposed in the past, such as miners, or populations which have suffered massive environmental exposure have not been adequately studied. However, the sparse epidemiologic data point toward the possibility of a risk of lung, kidney, and central nervous system tumors. Better data are needed on the carcinogenicity of mercury and mercury compounds in humans and experimental animals.

Animals↗
PubMed1993

Characterization of the human cytochrome P450 isozymes responsible for styrene metabolism.

The rate of formation of styrene glycol from styrene was compared in human, rat and mouse liver microsomes. At a low styrene concentration (0.085 mM), the rates decreased in the order, mouse > rat > human; at a high concentration (1.85 mM), the order was rat > mouse > human. The forms of cytochrome P450 that are responsible for transforming styrene to styrene glycol were determined by vaccinia virus-mediated cDNA expression of individual P450 forms in cultured cells. Of the 10 human P450 forms studied, CYP2B6 was the most effective in forming of styrene glycol, followed by CYP1A2, CYP2E1 and CYP2C8; the human P450s CYP3A3, CYP3A4 and CYP3A5 also catalysed metabolism, but were much less active; and CYP2A6, CYP2C9 and CYP2D6 had little detectable activity. CYP1A1 from mouse liver was more active in forming styrene glycol than mouse CYP1A2; the latter was less active than human CYP1A2. CYP2B1 from rat liver was more active than rat CYP2B2 or CYP2B6 from human liver. The rate of styrene glycol formation was higher in lung microsomes from smokers than in those from current nonsmokers.

Animals↗
PubMed1993

Occupational cancer in developing and newly industrialized countries.

Cancer is a worldwide public health problem, accounting for an increasing proportion of all deaths. It is the second leading cause of death in most of the industrialised world, and developing countries appear to be launched on a cancer epidemic, similar to that in industrialised countries. In developing countries, most cancer deaths are due to tumours of the stomach, oesophagus, lung, liver and uterine cervix; occupational cancers account for an undetermined number of these cases. Occupationally associated neoplasms may either be related directly to specific exposures within a workplace, e.g., bladder cancer in benzidine-exposed workers, or reflect indirect factors, including socioeconomic status and conditions of life. Asbestos-induced pneumoconiosis is recognised as an occupational disease in many developing countries, whereas asbestos-related malignancies draw less attention. The rising prevalence of cigarette smoking in these countries greatly magnifies the effect of asbestos in inducing lung cancer. Transplantation of industries from developed to developing countries is often accompanied by a reduction in the standard of working conditions. The rising unemployment in developing countries is unlikely to incite workers to claim better conditions.

Animals↗
PubMed1992

Serum oncoproteins and growth factors in asbestosis and silicosis patients.

Levels of 9 different oncoproteins and growth factors were assayed by immunoblotting with monoclonal antibodies in 91 serum samples collected between March 1983 and August 1987 from 46 pneumoconiosis patients (36 asbestosis, 10 silicosis) at high risk for the development of cancer. Follow-up of these patients through June 1991 showed that 18 had developed cancer (11 lung, 2 pleural mesothelioma, 2 transitional-cell carcinomas of the urinary bladder, 1 osteosarcoma, 1 non-Hodgkin's lymphoma, 1 adenocarcinoma of the gallbladder). Increased serum levels of ras oncogene-related protein (p21) were found in 7 of the 18 patients who developed cancer (5 lung, 2 pleural mesothelioma) versus 2 of the 28 patients without cancer, a statistically significant difference (p = 0.012). In addition, 6 of the 7 p21-positive cancer cases had positive serum samples prior to clinical diagnosis of disease (average = 16.3 months, range = 3-26 months prior to diagnosis), suggesting that elevated serum p21 levels may be a useful marker for earlier detection in a significant percentage of respiratory malignancies. Finally, elevated serum levels of PDGF-related protein were detected significantly more frequently in advanced pneumoconiosis cases (ILO radiographic classification of 2/1 or greater) than in less advanced cases (80% vs. 41.9%; p = 0.016), and there was a tendency for these PDGF-positive patients to have progression of their disease (68.2% vs. 41.7%; p = 0.065), suggesting that elevated serum PDGF levels may be a marker for the development of severe and progressive pneumoconioses.

Aged↗
PubMed1992

A comparative study on the contribution of cytochrome P450 isozymes to metabolism of benzene, toluene and trichloroethylene in rat liver.

The contribution of P450IIE1, P450IIC11/6, P450IIB1/2 and P450IA1/2 to the formation of chloral hydrate (CH) from trichloroethylene (TRI) was investigated in microsomes from control, ethanol-, phenobarbital (PB)- and 3-methylcholanthrene (MC)-treated rats using monoclonal antibodies (MAbs) to the respective P450 isozymes, and compared with their roles in benzene and toluene metabolism. Anti-P450IIE1 inhibited the formation of CH from TRI more strongly in microsomes from ethanol-treated rats than in microsomes from control rats at low concentration of TRI when net inhibition was compared. Anti-P450IIC11/6 inhibited CH formation in microsomes from control and PB-treated rats at high, not low, concentration of TRI, but the net inhibition in control microsomes was less than that due to anti-P450IIE1. Anti-P450IIB1/2 and anti-P450IA1/2 also inhibited CH formation from TRI in microsomes from PB- and MC-treated rats, respectively, stronger at high substrate concentration than at low concentration. These results indicate that P450IIE1, P450IIC11/6, P450IIB1/2 and P450IA1/2 are involved in the metabolic step from TRI to CH, and the first isozyme may be a low-Km TRI oxidase and the others high-Km one. Comparing the contributions of four isozymes to benzene, toluene and TRI metabolism, all four acted in the metabolism of these compounds, but P450IIE1 did not catalyse o-cresol formation nor P450IA1/2 benzyl alcohol formation from toluene, suggesting regioselectivity of toluene metabolism in the action of these two isozymes. The contribution of P450IIE1 in benzene and TRI oxidation was greater than that of P450IIC11/6, but the reverse was seen with respect to benzyl alcohol formation from toluene, indicating that P450IIC11/6 is relatively inactive towards benzene and TRI oxidation, but is primarily involved in toluene metabolism. P450IIB1/2 and P450IIC11/6 attacked all the metabolic positions studied, but only in the side-chain metabolism of toluene was their contribution significant, suggesting that these two isozymes are quite similar in function.

Animals↗
PubMed1992

Estimating human cancer risk from the results of animal experiments: relationship between mechanism and dose-rate and dose.

Experimental animals are often used as surrogate models in estimating human cancer risk from environmental agents when adequate epidemiological data are not available. Studies in experimental animals have usually evaluated the effects of exposure to single substances; however, humans receive combinations of exposures, to both initiators and promoters of carcinogenesis. Exposure to several agents may modify the carcinogenic process of one of them. For many agents, the relationship between dose and carcinogenic response depends on both dose-rate and cumulative dose. For a given total dose, dose-rate may affect carcinogenic potency both qualitatively (target organ) and quantitatively. The effects of dose-rate are a function of total dose, species, and most importantly, the mechanism by which the agent exerts its carcinogenic effect. Prediction of the effects of different dose-rates of potentially carcinogenic agents can be based on knowledge of its mechanism of action.

Animals↗