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Het sv-40 virus maakt muizen en hamsters extra gevoelig voorde schadelijke effecten van asbest. Amerikaanse en australische onderzoekers vonden bij hamsters en muizen dat het sv40-virus en het meest gevaarlijke blauwe asbest (crocidoliet), elkaar versterken in de mate waarin zij kankerverwekkend zijn. Het sv40-virus alleen veroorzaakte geen mesothelioom, het blauwe asbest alleen veroorzaakte mesothelioom bij 20% van de hamsters. Samen veroorzaakten het virus en de asbest mesothelioom bij 90% van de hamsters. De onderzoeksresultaten gaven aan dat mineraalvezels en virussen bij muizen en hamsters samen kankerverwekkend kunnen zijn en dat dragers van het sv40 virus gevoeliger kunnen zijn voor lagere doses asbestvezels. De vraag is of de werking bij mensen hetzelfde zal zijn. Dit zal nader onderzocht moeten worden. Het sv40 virus was oorspronkelijk een virus dat alleen bij apen voorkwam, maar maar bleek per abuis in de jaren 60 van de vorige eeuw ook in het poliovaccin te zitten. Bron: Kroczysnka, B. et al. (2006). Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters. Proceedings of the National Academy of Sciences of the United States of America, 103.14128-14133. originally published online Sep 11, 2006. Robinson, C. et al. (2006). A novel SV40 tag transgenic model of asbestos-induced mesothelioma: Malignant Transformation Is Dose Dependent. Cancer Res, 66, 10786-94.

Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters

Abstract

Only a fraction of subjects exposed to asbestos develop malignant mesothelioma (MM), suggesting that additional factors may render some individuals more susceptible. We tested the hypothesis that asbestos and Simian virus (SV40) are cocarcinogens. Asbestos and SV40 in combination had a costimulatory effect in inducing ERK1 2 phosphorylation and activator protein-1 (AP-1) activity in both primary Syrian hamster mesothelial cells (SHM) and primary human mesothelial cells (HM). Ap-1 activity caused the expression and activation of matrix metalloprotease (MMP)-1 and MMP-9, which in turn led to cell invasion. Experiments using siRNA and chemical inhibitors confirmed the specificity of these results. The same effects were observed in HM and SHM. Experiments in hamsters showed strong cocarcinogenesis between asbestos and SV40: SV40 did not cause MM, asbestos caused MM in 20% of hamsters, and asbestos and SV40 together caused MM in 90% of hamsters. Significantly lower amounts of asbestos were sufficient to cause MM in animals infected with SV40. Our results indicate that mineral fibers and viruses can be cocarcinogens and suggest that lower amounts of asbestos may be sufficient to cause MM in individuals infected with SV40.

Robinson, C. et al. (2006). A novel SV40 tag transgenic model of asbestos-induced mesothelioma: Malignant Transformation Is Dose Dependent. Cancer Res, 66, 10786-94.

Abstract

Although it has been clear for >40 years that mesothelioma can be caused by asbestos, not all patients with this disease have a history of asbestos exposure. Other factors, including non-asbestos fibers and ionizing radiation, are known to cause malignant transformation of mesothelial cells. In addition, it is likely that genetics will play some role in susceptibility. Recently, it has been suggested that SV40 viral oncogenes could contribute to the carcinogenicity of asbestos. To better understand the role of SV40, we used the mesothelin promoter to construct MexTAg mice that express SV40 large T antigen (TAg) in the mesothelial compartment. We generated four MexTAg lines that carry high, intermediate, and low copy numbers of the transgene. All of these mice show a relatively low level of spontaneous tumor development. High-copy, 299h mice rapidly developed mesotheliomas when exposed to asbestos, and these tumors were faster growing and more invasive than those developing in wild-type and single-copy (266s) mice. In addition, we found a direct relationship between transgene copy number and survival after exposure to asbestos. A single copy of TAg was sufficient to immortalize mesothelial cells in vitro, but these cells did not show evidence of malignant transformation. In contrast, cell lines developed from mesothelial cells of animals carrying multiple copies of TAg were growth factor independent and could be cloned at

limiting dilution in soft agar. These data provide the first in vivo demonstration of co-carcinogenicity between SV40 and asbestos.

Veel mensen zijn intensief in contact met asbest geweest. Een klein aantal van hen krijgt mesothelioom. Drie recent gepubliceerde studies wijzen erop dat erfelijke aanleg een verhoogde gevoeligheid kan geven voor het krijgen van deze aandoening. In een Italiaans onderzoek werd een verhoogde kans op mesothelioom gevonden bij mensen met een lage activiteit van het mEH-enzym. Turkse onderzoekers vonden dat mesothelioom in bepaalde families wel voorkomt en in andere families niet, terwijl de blootstellingsniveaus aan erioniet, een asbestachtig materiaal, gelijk waren. Amerikaanse onderzoekers vergeleken een groep mesothelioompatiënten met drie andere groepen asbestblootgestelden. De mesothelioompatiënten hadden meer eerstelijns-familieleden met kanker en bij hen was vaker een tweede kanker vastgesteld. Bron: Laan, G. van der (2006). Asbestkanker en genethisch bepaalde gevoeligheid. TBV 14, 7, september 2006, pag. 298. Ohar, J.A. et al. (2006). Identification of a mesothelioma phenotype. Respitory Medicine, article in press.
Neri, M., Filiberti, R, Taioli, E. et al., (2005). Pleural malignant mesothelioma, genetic susceptibility and asbestos exposure. Mutat Res , 592, 36-44.

Abstract

Pleural malignant mesothelioma (MM) is a rare but extremely aggressive cancer. The limited impact of standard therapeutic treatments on survival rates makes the identification of factors that increase the individual risk a leading priority. The high proportion of cases explained by exposure to asbestos has guided intervention policies to an effective ban of this compound from our environment. However, MM cannot be solely attributed to this agent, and the role of predisposing factors and their interaction with asbestos exposure is increasingly studied. The role of mEH, GSTM1, GSTT1, NAT2, and CYP1A1 genotypes in modulating susceptibility to MM was examined in a case-control study of 80 subjects with a confirmed diagnosis of MM and 255 controls. Subjects with low mEH activity showed a significantly increased risk of MM (OR, 2.51. 95% CI, 1.11-5.68). The association was stronger in the group with low asbestos exposure (OR, 7.83. 95% CI, 0.98-62.60). A significant increased risk of MM was also found in NAT2 fast acetylators (OR, 1.74. 95% CI, 1.02-2.96). The presence of synergisms between genotypes, i.e., mEH and NAT2 (LRT for heterogeneity p<0.023), mEH and GSTM1 (LRT p<0.061), and NAT2 and GSTM1 (LRT p<0.049), combined with the interaction observed with exposure to asbestos, suggests the presence of gene-environment and gene-gene interactions in the development of MM, although the size of the study group does not allow to draw clearcut conclusions. Since genetic polymorphisms can also modify the extent of genetic damage occurring in subjects exposed to carcinogens, we measured the frequency of micronuclei in peripheral blood lymphocytes of a subgroup of MM cases. The limited number of cases (28) did not allow to observe significant effects. In conclusion, these results strengthen the hypothesis that individual susceptibility to MM can be modulated by the interaction between polymorphic genes involved in the metabolism and the intensity of asbestos exposure. Dogan AU, Baris YI, Dogan M, Emri S, Steele I, Elmishad AG, Carbone M., (2006). Genetic predisposition to fiber carcinogenesis causes a mesothelioma epidemic in Turkey. Cancer Research, mei 15.66(10):5063-8.

Abstract

Malignant mesothelioma in the western world is often associated with asbestos exposure. It is a relatively rare cancer that causes approximately 2,500 deaths yearly in the United States and 1,000 deaths yearly in the United Kingdom. In contrast, among people born in the Cappadocian (Turkey) villages of Tuzkoy, Karain, and “Old” Sarihidir, approximately 50% of deaths are caused by malignant mesothelioma. This epidemic has been attributed to erionite exposure, a type of fibrous zeolite mineral commonly found in this area of Turkey. In these three villages, malignant mesothelioma occurs in certain houses but not in others. The hypothesis was that a unique and more carcinogenic erionite was present in certain houses and caused malignant mesothelioma. We determined the X-ray diffraction pattern and the crystal structure of erionite from malignant mesothelioma villages and compared the results with the erionite samples from nearby non-malignant mesothelioma villages and from the United States. We found the same type of erionite in Cappadocian villages, with or without a malignant mesothelioma epidemic, in households with high or no incidence of malignant mesothelioma and in the United States. Pedigree studies of the three malignant mesothelioma villages showed that malignant mesothelioma was prevalent in certain families but not in others. When high-risk malignant mesothelioma family members married into families with no history of it, malignant mesothelioma appeared in the descendants. Genetically predisposed family members born and raised outside the malignant mesothelioma villages did not seem to develop malignant mesothelioma. In summary, pedigree and mineralogical studies indicate that the malignant mesothelioma epidemic is caused by erionite exposure in genetically predisposed individuals. This is the first time that genetics is shown to influence mineral fiber carcinogenesis.

Ohar, J.A. et al. (2006). Identification of a mesothelioma phenotype. Respitory Medicine, article in press.

Abstract

Despite the strong association of asbestos exposure to mesothelioma, only a fraction of persons exposed develop this neoplasm which is characterized by long latency and shortened survival. Familial clustering implicates both exposure and genetic predisposition as causative, but a biologically relevant mesothelioma phenotype essential to genetic analysis has not been defined. To identify a more extensive set of traits that would define a mesothelioma phenotype for the purpose of genetic analysis, we set to determine characteristics that distinguish mesothelioma patients from others exposed to asbestos and to identify factors that predict the presence of mesothelioma over other mesenchymal tumors of the peritoneum and carcinoma metastatic to the pleura. We compared demographics in four asbestos-exposed groups (controls n=347, bronchogenic cancer n=67, mesothelioma n=179 and benign asbestos-induced lung disease (BALD) n=3757). Within the mesothelioma group, we compared traits to identify characteristics associated with shortened survival. We found that compared to other asbestos-exposed groups, subjects with mesothelioma were younger at first asbestos exposure, had a greater risk of a second cancer diagnosis (odds ratio=3.29), had a longer disease latency, and had a greater risk of cancer among first-degree relatives (point estimate for risk 2.93. 95% CI 2.5-3.5). Thoracic tumor location, work exposure and male gender were consistently associated with shortened survival (1.9+/-1.3 years). We conclude that thoracic tumor location, work exposure, male gender, long latency, early age at first exposure, presence of a second cancer, and first-degree relative with cancer define a phenotype that sets mesothelioma patients with a short survival apart from other asbestos-exposed individuals. We propose that this phenotype be applied to candidate gene analysis.

In het Australische Perth wordt binnenkort een nieuw landelijk centrum opgericht voor onderzoek naar asbestgerelateerde ziekten. De Australische regering verleent hiervoor een subsidie van bijna 4 miljoen euro. In Japan gaat dit najaar het eerste centrum voor onderzoek naar en behandeling van mesothelioom open. Het zal gevestigd worden in de Hyogo prefectuur, een regio waar veel asbestziekten voorkomen omdat de vroegere asbestfabriek Kuboto er gevestigd was. Bron: The Yomiuri Shimbun, 24 augustus 2006, The West Australian, 27 september 2006.

Alle Japanners die in het verleden met asbest hebben gewerkt hebben sinds november recht op gratis medisch onderzoek. Tot nu toe werd deze service alleen geboden door bedrijven aan hun (ex-)werknemers. De overheid biedt deze service nu ook aan ex-werknemers van een bedrijf dat niet meer bestaat. Het ministerie van Volksgezondheid schat dat bijna 30.000 mensen gebruik zullen maken van dit aanbod. Bron: The Yomiuri Shimbun, 6 oktober 2006.

Oxidanten in sigarettenrook en asbestvezels kunnen de werking van het MAPK eiwit zodanig ontregelen dat er een wildgroei van cellen op gang komt die tot vorming van een longtumor kunnen leiden. De asbestvezels en sigarettenrook versterken elkaar in deze werking. Dit schrijven Amerikaanse onderzoekers in de “American Journal of Respiratory Cell and Molecular Biology”. Dit proces verklaart het vaker voorkomen van longkanker bij mensen die met asbest werkten en roken. Bron: Mossman BT. et al. (2006). Oxidants and signaling by mitogen-activated protein kinases in lung epithelium. American Journal of Respiratory Cell and Molecular Biology,Jun.34(6):666-9.
Mossman BT, Lounsbury KM, Reddy SP. (2006). Oxidants and signaling by mitogen-activated protein kinases in lung epithelium. American Journal of Respiratory Cell and Molecular Biology,Jun.34(6):666-9.

Abstract

Oxidants in cigarette smoke and generated from asbestos fibers activate mitogen-activated protein kinase (MAPK) signaling cascades in lung epithelial cells in vitro and in vivo. These signaling pathways lead to the enhanced ability of Jun and Fos family members (i.e., components of the activator protein [AP]-1 transcription factor) to activate transcription of a number of AP-1-dependent target genes involved in cell proliferation or death, differentiation, and inflammation. Research by the Basbaum laboratory has been critical in showing that mucin transcription in response to cigarette smoke and gram-positive bacteria is mediated through activation of the epidermal growth factor receptor and MAPK cascades. Work from our laboratories supports the concept that MAPK signaling and AP-1 transactivation by cigarette smoke and asbestos may synergize in lung epithelial cell injury, compensatory proliferation of lung epithelial cells, and carcinogenesis, supporting a mechanistic framework for the striking increases in lung cancer incidence in asbestos workers who smoke. Targeting of MAPKs and inter-related signaling cascades may be critical to the prevention of lung cancers and control of mucin overproduction in a number of lung diseases including asthma, cystic fibrosis, chronic bronchitis, and chronic obstructive pulmonary disease.

In de herfst zal in Japan het eerste centrum voor onderzoek naar en behandeling van mesothelioom open gaan. Het zal gevestigd worden in de Hyogo prefectuur, een regio waar veel asbestziekten voorkomen omdat de vroegere asbestfabriek Kuboto er gevestigd was. Bron: The Yomiuri Shimbun, 24 augustus 2006.

De Amerikaanse “Food and Drug Administration” (FDA) heeft farmaceut Ei Lilly gewezen op onvolledigheden in de brochure over het medicijn Alimta dat gebruikt wordt in de behandeling van mesothelioom en kleincellige longkanker. De brochure vermeldt bijvoorbeeld niet voor welke vormen van kanker Alimta gebruikt mag worden. Noch wordt gewezen op de fatale gevolgen die Alimta tijdens zwangerschap op de foetus kan hebben. In 2005 heeft Ei Lilly 463 miljoen Us dollar omgezet in de verkoop van Alimta. Bron: mesotheliomaweb.org, 1 augustus 2006. Meer http://www.mesotheliomaweb.org/fdawarning.htm

Amerikaanse onderzoekers hebben een relatie gevonden tussen blootstelling aan asbest en bepaalde huidziektes en reuma. Zij bestudeerden 7307 huidige en voormalige inwoners van het voormalige mijnstadje Libby in Montana, waar in de mijnen met asbest vervuild vermiculiet werd gewonnen. Inmiddels zijn al 1500 mensen ziek geworden. De onderzoekers constateerden dat oudere (ex-)mijnwerkers drie keer zoveel risico hebben op het krijgen van reuma en twee keer zoveel kans op auto-immuunziekten in het algemeen. Ook inwoners van Libby die niet in de mijnen hadden gewerkt, maar in het leger aan asbest waren blootgesteld, hadden een verhoogd risico op auto-immuunziekten. Meer onderzoek is nodig. Bron: Noonan, C.W. (2006). Nested case-control study of autoimmune disease in an asbestos-exposed population. Environ Health Perspective Aug.114(8):1243-7.
Noonan CW, Pfau JC, Larson TC, Spence MR., (2006). Nested case-control study of autoimmune disease in an asbestos-exposed population. Environ Health Perspective Aug.114(8):1243-7.

OBJECTIVE: To explore the potential association between asbestos exposure and risk of autoimmune disease, we conducted a case-control study among a cohort of 7,307 current and former residents of Libby, Montana, a community with historical occupational and environmental exposure to asbestos-contaminated vermiculite. METHODS: Cases were defined as those who reported having one of three systemic autoimmune diseases (SAIDs): systemic lupus erythematosus, scleroderma, or rheumatoid arthritis (RA). Controls were randomly selected at a 3:1 ratio from among the remaining 6,813 screening participants using frequency-matched age and sex groupings. RESULTS: The odds ratios (ORs) and 95% confidence intervals (CIs) for SAIDs among those >or=65 years of age who had worked for the vermiculite mining company were 2.14 (95% CI, 0.90-5.10) for all SAIDs and 3.23 (95% CI, 1.31-7.96) for RA. In this age group, exposure to asbestos while in the military was also an independent risk factor, resulting in a tripling in risk. Other measures of occupational exposure to vermiculite indicated 54% and 65% increased risk for SAIDs and RA, respectively. Those who had reported frequent contact with vermiculite through various exposure pathways also demonstrated elevated risk for SAIDs and RA. We found increasing risk estimates for SAIDs with increasing numbers of reported vermiculite exposure pathways (p<0.001). CONCLUSION: These preliminary findings support the hypothesis that asbestos exposure is associated with autoimmune disease. Refined measurements of asbestos exposure and SAID status among this cohort will help to further clarify the relationship between these variables.

De Britse gezondheidsautoriteit Nice heeft de vergoeding van het medicijn Alimta (pemetrexed) voor mesothelioom afgewezen. Dit op basis van het argument dat er niet genoeg bewijs is dat behandeling met dit medicijn beter werkt dan voordeliger behandelingen. Dit betekent dat de National Health Service NHS het middel niet meer zal vergoeden. Fabrikant Ei Lilly gaat tegen deze beslissing in beroep. Bron: Daily Telegraph, 3 juli 2006, newsinferno.com, 28 juni 2006. Meer http://www.newsinferno.com/archives/1198

De extra kans op longkanker van iemand die én heeft gerookt én asbestvezels heeft ingeademd is meer dan een optelling, maar minder dan het product van de verhoging bij alleen roken en die bij alleen asbestblootstelling. Dit concluderen Wraith en Mengersen na een meta-analyse van de literatuur met behulp van de Bayesiaanse benadering, een statistische methode. Bron: Wraith D. & Mengersen K. (2006). Assessing the combined effect of asbestos exposure and smoking on lung cancer: a Bayesian approach. Statistics in Medicine, june 16.

Bron: Wraith D. & Mengersen K. (2006). Assessing the combined effect of asbestos exposure and smoking on lung cancer: a Bayesian approach. Statistics in Medicine, june 16.

Abstract

We review the literature on the combined association between lung cancer and two environmental exposures, asbestos exposure and smoking, and explore a Bayesian approach to assess evidence of interaction between the exposures. The meta-analysis combines separate indices of additive and multiplicative relationships and multivariate relative risk estimates. By making inferences on posterior probabilities we can explore both the form and strength of interaction. This analysis may be more informative than providing evidence to support one relation over another on the basis of statistical significance. Overall, we find evidence for a more than additive and less than multiplicative relation. Copyright (c) 2006 John Wiley & Sons, Ltd.