asbestos--crocidolite and Cocarcinogenesis

Simian virus 40 (SV40) has been implicated in the development of several cancers including malignant mesothelioma. A definitive role for the virus in human mesothelioma has not been unequivocally demonstrated but has been rigorously debated. The virus clearly has oncogenic potential: the TAg is one of the most potent transforming proteins known and acts synergistically with crocidolite asbestos to transform mesothelial cells. In this study, we show that SV40 oncogenes alone can cause malignant transformation and that asbestos-induced DNA damage and apoptosis occurs principally in cycling cells. After long-term exposure (up to 100 days) to both SV40 and asbestos, cells become resistant to stress-induced senescence. Significantly, these cells demonstrate resistance to chemotherapy-induced apoptosis. This finding has implications for the development of effective treatment options for patients with mesothelioma.

Topics: Animals; Antigens, Polyomavirus Transforming; Apoptosis; Asbestos, Crocidolite; Blotting, Western; Cell Adhesion; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Cocarcinogenesis; Drug Resistance, Neoplasm; Humans; Immunoenzyme Techniques; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peritoneum; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Malignant mesothelioma has been linked to asbestos exposure and generally has a poor prognosis because it is often diagnosed in advanced stages and is refractory to conventional therapy. Human malignant mesotheliomas accumulate multiple somatic genetic alterations, including inactivation of the NF2 and CDKN2A/ARF tumor suppressor genes. To better understand the significance of NF2 inactivation in malignant mesothelioma and identify tumor suppressor gene alterations that cooperate with NF2 loss of function in malignant mesothelioma pathogenesis, we treated Nf2 (+/-) knockout mice with asbestos to induce malignant mesotheliomas. Asbestos-exposed Nf2 (+/-) mice exhibited markedly accelerated malignant mesothelioma tumor formation compared with asbestos-treated wild-type (WT) littermates. Loss of the WT Nf2 allele, leading to biallelic inactivation, was observed in all nine asbestos-induced malignant mesotheliomas from Nf2 (+/-) mice and in 50% of malignant mesotheliomas from asbestos-exposed WT mice. For a detailed comparison with the murine model, DNA analyses were also done on a series of human malignant mesothelioma samples. Remarkably, similar to human malignant mesotheliomas, tumors from Nf2 (+/-) mice showed frequent homologous deletions of the Cdkn2a/Arf locus and adjacent Cdkn2b tumor suppressor gene, as well as reciprocal inactivation of Tp53 in a subset of tumors that retained the Arf locus. As in the human disease counterpart, malignant mesotheliomas from the Nf2 (+/-) mice also showed frequent activation of Akt kinase, which plays a central role in tumorigenesis and therapeutic resistance. Thus, this murine model of environmental carcinogenesis faithfully recapitulates many of the molecular features of human malignant mesothelioma and has significant implications for the further characterization of malignant mesothelioma pathogenesis and preclinical testing of novel therapeutic modalities.

Topics: Animals; Asbestos, Crocidolite; Cocarcinogenesis; Disease Models, Animal; Genes, Neurofibromatosis 2; Genes, p53; Genetic Predisposition to Disease; Humans; Mesothelioma; Mice; Mice, Knockout; Tumor Suppressor Protein p14ARF

An implant can act as a physical carcinogen. Chemicals applied to its surface can augment that. To explore if cocarcinogenesis would affect the incidence of tumour on implants, we tested several physical (asbestos, beta irradiation) and chemical (acridine orange, phorbol methyl ester, cigarette smoke tar, extract of Agaricus bisporus mushroom) carcinogens on 25 mm diameter nitrocellulose filters implanted in groups of BALB/c mice in 9 experiments. Saline was applied in 287 concurrent controls. Irradiation by 540 kBq I-125 fibrinogen on foreign bodies of surface area 20sq cm induced tumour in 6/6 pilot animals (expected 2/6) and in 25/36 animals (controls 13/29; p < 0.04). The mean dose (beta and gamma) to cells within 20 microm of the filter surface was estimated to be 782 mGy. Exposures to 270kBq or less were not significantly cocarcinogenic with single implants. Radiation from the paired implants was detectible up to 80 weeks. Asbestos, however, 2.3 or 4.6 mgm on implants did not in 3 trials increase sarcoma yield significantly, but did induce mesothelial-type growths in the peritoneum. Asbestos (2.3 mg) injected without an implant provoked no tumour at the site. The chemical carcinogen acridine orange gave ambiguous results, and the others reduced tumour incidence insignificantly. The irradiation history may be germane in the human cases that arise.

Topics: Animals; Asbestos, Crocidolite; Carcinogens; Cocarcinogenesis; Collodion; Fibrosarcoma; Humans; Male; Mice; Mice, Inbred BALB C; Micropore Filters; Prostheses and Implants; Radiation Dosage; Radiation, Ionizing

Recently, there has been concern that ingested asbestos may cause an increase in cancer incidence in populations exposed to fibre-contaminated drinking water. Although animal experiments failed to demonstrate carcinogenicity of the oral asbestos exposure, the high adsorption capacity of the fibres creates the possibility of cocarcinogenic action with adsorbed organics. In a simple in vivo model we demonstrated earlier that UICC crocidolite and anthophyllite asbestos fibres were able to adsorb carcinogen molecules from aqueous solutions. When orally administered, these fibres increased the sister chromatid exchange frequency in bone marrow cells of rats. In the present study we tried to follow the desorption and metabolization processes of carcinogenic benzo[a]pyrene molecules transported by the ingested fibres using the highly sensitive Salmonella/Ames mutagenicity assay. The bacterial test was performed on concentrated serum and urine samples of the treated animals by using the TA98 and 100 strains in the presence and absence of liver microsomal and deconjugating enzymes. All sets of urine and serum samples failed to show mutagenic activity indicating a lack of both desorption in the serum and the ability of the liver to metabolize. Considering our results, the cytogenetic impact demonstrated earlier in the bone marrow can be explained by a local action of accumulated and transported carcinogen molecules.

Topics: Animals; Asbestos, Amphibole; Asbestos, Crocidolite; Benzo(a)pyrene; Carcinogens; Cocarcinogenesis; Female; Mutagenicity Tests; Mutagens; Rats; Rats, Inbred F344

Epidemiological reports have indicated that occupational exposure to asbestos and smoking may greatly increase the incidence of lung carcinoma. In this study rats were injected intratracheally with crocidolite or benzo(a)pyrene [B(a)P] only, and crocidolite plus B(a)P in combination. The incidence of lung carcinomas in crocidolite group was 6.4% (3/47), in B(a)P group 10.4% (5/48) and crocidolite plus B(a)P group 46.3% (25/54). Besides, the survival curve and the mean survival time of rats with carcinoma dropped distinctly. Significant difference was shown among the crocidolite plus B(a)P group, crocidolite and B(a)P groups (P < 0.005). The result indicated the synergetic effect of crocidolite and B(a)P on the development of lung carcinoma in rats and the importance of giving up smoking in the people exposed to asbestos. A model of lung carcinoma in rat was successfully prepared for further study in experiment on treatment, prevention and mechanism.

Topics: Animals; Asbestos, Crocidolite; Benzo(a)pyrene; Carcinogens; Cocarcinogenesis; Disease Models, Animal; Lung Neoplasms; Rats; Rats, Wistar; Smoking

The results of our in vitro study showed that Rhodesia chrysotile, X. K. chrysotile, UICC chrysotile, crocidolite and amosite could cause damage to calf thymus DNA by inducing the production of 8-hydroxy-2'-deoxyguanosine (8-OH-dG). After adding H2O2 and/or FeSO4, the production of 8-OH-dG, induced by asbestos fibers was significantly increased. The fiber of UICC crocidolite has the most untoward effect, that of UICC amosite comes next, and the three chrysotile fibers are the weakest ones. The effect of asbestos fibers on the production of 8-OH-dG has some relationship with hydroxy free radical and the type of asbestos. It is suggested that asbestos fibers could induce DNA point mutation through A.T and G.C transversion by the production of 8-OH-dG, which is related with the carcinogenesis of asbestos.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Cattle; Cocarcinogenesis; Deoxyguanosine; DNA; DNA Damage; Drug Synergism; Hydrogen Peroxide; In Vitro Techniques; Iron Compounds

Environmental carcinogenesis in man is widely accepted to be a multifactorial process, and in the causation of lung cancers it is suspected that low levels of systemic carcinogens may act synergistically with inhaled particulates so that some exposed individuals are at increased risk. In the present study the carcinogenic effects of low levels of industrially and environmentally significant particulate materials (crocidolite asbestos and metallic cadmium) and a putative systemic carcinogen, N-nitrosoheptamethyleneimine (NHMI), were investigated in the laboratory rat, using this as a model of potential human exposure. The overall lung tumour incidence rate in the group of animals receiving crocidolite, cadmium and NHMI (14/45) was significantly higher than in the groups of animals receiving either crocidolite and cadmium together (2/51) or crocidolite and NHMI together (7/42). The results demonstrated an apparent synergy between cadmium and NHMI in the presence of crocidolite in the causation of lung cancer in rats, a finding which was confirmed statistically. This study helps to further evaluate and define the roles of asbestos and particulate cadmium in the causation of lung cancer. It is suggested that people who are exposed through occupation and/or environment to cadmium and asbestos and to low levels of systemic carcinogens may show a significantly elevated risk of lung cancer.

Topics: Animals; Asbestos; Asbestos, Crocidolite; Cadmium; Carcinogens; Cocarcinogenesis; Environmental Exposure; Female; Lung Neoplasms; Nitrosamines; Rats

Topics: Animals; Asbestos; Asbestos, Crocidolite; Carbon; Cells, Cultured; Cocarcinogenesis; Cricetinae; Dust; Ferric Compounds; Kaolin; Mesocricetus; Methylcholanthrene; Minerals; Neoplasms, Experimental; Tracheal Neoplasms