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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Formaldehyde is a widespread animal carcinogen with limited evidence of carcinogenesis in humans. We investigated the occupational risk of cancer (1970-84) among men and women in Denmark. Relative risks (RR) were estimated from standardized proportionate incidence ratios among patients whose longest employment had been held since 1964, at least 10 years before diagnosis, in 265 companies in which exposure to formaldehyde was identified. The only biologically plausible increased risk was for nasal cancer, for which relative risks of 2.3 (95% confidence interval = 1.3-4.0) and 2.4 (0.6-6.0) appeared for men and women, respectively. In the subgroup of blue-collar men with no probable exposure to wood-dust, the major confounder, the relative risk for this cancer was 3.0 (1.4-5.7). It is concluded that occupational exposure to formaldehyde may increase the risk of nasal cancer, but formaldehyde does probably not affect other cancers.
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PMID:[Occupational exposure to formaldehyde and risk of cancer]. 870 36

Hydrazine, which is toxic and carcinogenic to rodent liver, has been shown to react with endogenous formaldehyde in the liver to form formaldehyde hydrazone (CH2 = N-NH2), an alkylating intermediate that methylates DNA guanine at the N7- and O6-positions. Studies were conducted to investigate the role of chronic hydrazine-induced hepatotoxicity on DNA maintenance methylation (formation of 5-methyldeoxycytosine) and the development of liver cancer. Male Syrian golden hamsters were given hydrazine sulfate (0, 170, 340 and 510 mg/l) in drinking water for 21 months (average dose 0, 4.2, 6.7 and 9.8 mg/kg body wt hydrazine as the free base). Hepatotoxicity was evaluated histologically, and regenerative DNA synthesis and maintenance methylation were measured as the incorporation of [methyl-14C]thymidine into DNA and the methyl moiety of [methyl-3H]methionine into 5-methyldeoxycytosine in DNA, respectively. Methylguanines were detected in liver DNA at the first observation time of 6 months of treatment; levels of these aberrant bases decreased or became undetectable at 14 months, and increased in a dose-related manner for the remainder of the study. DNA adducts persisted in the highest dose group throughout the study, repeating the results of a similar study previously reported by this laboratory (Bosan et al., Carcinogenesis, 8, 439-444, 1987). Linear regression analysis of thymidine and methionine methyl moiety incorporation into liver DNA suggested impairment of maintenance methylation of DNA (5-methyldeoxycytosine) in the middle and high exposure animals. Hepatic adenomas and hepatocellular carcinomas developed in a dose-related manner and were highly correlated to decreased uptake of radiolabel from methionine into DNA 5-methylcytosine. These results are part of a continuing study on alteration of maintenance methylation during hydrazine induction of liver cancer.
Carcinogenesis 1996 Dec
PMID:Methylation status of DNA cytosine during the course of induction of liver cancer in hamsters by hydrazine sulfate. 900 9

The 1980 report that inhaled formaldehyde induced nasal squamous cell carcinomas in rats had a significant societal impact and resulted in extensive research in the fields of rodent nasal pathology and human cancer risk assessment. This article presents an overview of the evolution of these events. It is concluded that the nasal passages of humans and rats are fundamentally identical biological target organs. Nevertheless, in the case of human health risk assessment, minor differences between these species may be critically important. Special attention should be paid to interspecies differences in nasal dosimetry and local metabolism; thus, chemical toxicity data derived from rats require careful interpretation when used for human risk assessments. In the case of formaldehyde, it is recommended that low-concentration (< or = 2 ppm airborne exposure) extrapolation, where no tissue damage is observed, be uncoupled from the responses at high concentrations (> or = 6 ppm), where epithelial degeneration, regenerative cell replication, and inflammation appear to be essential driving forces in formaldehyde carcinogenesis. The presence of treatment-related nasal lesions in rats following exposure to chemicals should always be treated as an indication of a potential human health risk, whether exposure is by the inhalation, oral, or dermal route.
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PMID:A brief review of formaldehyde carcinogenesis in relation to rat nasal pathology and human health risk assessment. 921 Feb 61

The ability to isolate DNA from archived human serum, plasma and paraffin-embedded human tissues enhances opportunities to study breast, lung and other cancer risk factors. We report herein a simple and fast protocol for the extraction of genomic DNA from these sources. Using a phenol-based extraction method, the recovery for DNA is quantitative and reproducible. DNA yields in serum (250 microl) were between 162 and 1060 ng (n = 18 subjects), in plasma (250 microl) were between 165 and 375 ng (n = 5 subjects) and in embedded tissues (5-microm thick sections for ethanol fixed, and between 5- and 20-microm sections for formaldehyde fixation) were between 1 microg and 11.7 microg (n = 32 subjects). The extraction method was combined with newly designed PCR-based assays for cancer susceptibility marker genes such as CYP1A1 (exon 7), CYP2E1 (Dra1, Rsa1), GSTM1 and NAT2 [NAT2*5A (C481T), NAT2*6A (G590A), NAT2*7A (G857A)]. Genotyping results from the serum and paraffin-embedded tissues compared favorably to results from archived freshly frozen tissues, where concordance was 98% for serum, 100% for ethanol-fixed embedded tissues, and 97% for formaldehyde-fixed and paraffin-embedded tissues. This facile method will allow for the use of archived tissue samples of prospective cohort and other studies where intact DNA was not previously available.
Carcinogenesis 1997 Jun
PMID:Serum, plasma and paraffin-embedded tissues as sources of DNA for studying cancer susceptibility genes. 921 13

An increased rate of cell proliferation has long been recognized as an important factor in both human and experimental carcinogenesis, and may be a major risk factor for cancer development in a number of tissues. Limited information exists, however, regarding the relevance of increased cell proliferation and nasal cancer. Examples of toxicological studies utilizing nasal cell proliferation data as an important endpoint are briefly reviewed. Data for one of the most extensively studied chemicals, the weakly genotoxic carcinogen formaldehyde, support the contention that the concentration-response relationship for tumor incidence is a function of formaldehyde-induced target cell proliferation, in addition to other factors including target cell population size. The increasing importance of utilizing cell proliferation data in determining dose-response relationships and in biologically-based risk assessment models is discussed.
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PMID:Chemically-induced nasal carcinogenesis and epithelial cell proliferation: a brief review. 938 88

Bis-Chloro-Methyl-Ether is an alkylating agent and a recognised carcinogen. It can form spontaneously from the reaction of chloridric acid with formaldehyde. In the past it was extensively used as a chemical intermediate in organic synthesis, particularly as a crosslinking agent in the manufacture of ion-exchange resins. Recently, since its carcinogenicity has been proved in animal studies and confirmed in epidemiological studies of occupationally exposed cohorts, its use has been consistently reduced. A characteristic association has been observed between BCME exposure and a peculiar lung cancer histotype (oat cell carcinoma). In spite of these data, little information is available on the molecular alterations related to BCME exposure and possibly to its carcinogenic activity. Some suggestions can reasonably be obtained considering how the class of alkylating agents acts. They form adducts, binding different positions of DNA bases. The reaction that seems more relevant for mutagenesis and carcinogenesis is the alkylation at the atom O6 of guanine in DNA, which is followed by mis-coding and GC-->AT transition mutation. This kind of alteration determines the activation of a group of enzyme like DNA repair, mismatch repair, excision repair and a specific one, methyl guanine methyl transferase (MGMT). This last repair protein transfers alkyl groups from the O6 position of guanine to an internal cysteine residue, inactivating itself. Thus, the possibility for the cell to eliminate alkylated DNA bases depends strictly upon the cellular content of MGMT. In this view reduced or absent levels of the enzyme are associated with an increased number of adducts and hence increased risk of DNA mutations and cancer. At the moment no molecular studies in vivo have been performed to verify this hypothesis. The peculiar association BCME-oat cell carcinoma, the most chemosensitive tumor, need further investigation.
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PMID:[Bis-chloromethyl ether and carcinogenesis of alkylating agents]. 948 99

Clonality of invasive human cervical cancer was assessed in microdissected archival formaldehyde-fixed, paraffin-embedded tissues by PCR-based analysis of X-chromosome inactivation of the androgen receptor gene. In 18 informative cases, cancers from 12 cases including 2 early-invasive cancers were scored as monoclonal. Among them, 8 cases had the combination of random X-chromosome inactivation in normal cervical tissue and non-random in the cancer and in other 4 cases normal and cancer tissue were both non-random but had discordant X-chromosome inactivation. Six cases showed that the non-random inactivation affected the same allele in cancer and normal tissue and thus were considered to be inconclusive. The results suggest the monoclonal origin of cervical cancer and indicate that genetic events are critical in transition of pre-malignant epithelia to invasive cancer in cervical carcinogenesis. Finding of monoclonal early invasive cancer also argues that monoclonality of human tumors is not a late event due to clonal competition or selection. X-chromosome inactivation patterns in normal cervical epithelia and tissues were analyzed in 21 informative cases. When a mixture of normal stroma and epithelium was analyzed, 38% (8/21) of cases showed non-random inactivation pattern, whereas using pure epithelium it was 64% (11/17). The X-chromosome inactivation pattern between mixed epithelium/stroma and matched epithelium differed in 2/8 cases. These results point to a certain amount of overlooked source of error in X-inactivation-based tumor clonality analysis in which peripheral blood monocytes were chosen as control and strongly recommend that control tissues which share close histological origin with analyzed tumors should be selected in any clonality study of human neoplasm. Post-embryological mechanisms of clonal patch in normal cervical epithelia are also discussed.
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PMID:Clonality analysis of cervical cancer on microdissected archival materials by PCR-based X-chromosome inactivation approach. 959 94

The shape of a carcinogen dose-cancer incidence curve is discussed as the result of a superposition of dose-response relationships for various effects of the carcinogen on the process of carcinogenesis. Effects include direct DNA damage, e.g., by covalent binding, indirect DNA damage, e.g., by increased formation of reactive oxygen species or interaction with DNA replication or chromosome integrity. The 'fixation' of a DNA adduct as a heritable mutation depends on its pro-mutagenic potency and on the rates of DNA repair and DNA replication. Endogenous and unavoidable DNA damage is responsible for a background rate of the process of mutagenesis and carcinogenesis and forms the basis of spontaneous cancer incidence. For DNA-reactive carcinogens, linearity of the dose response at the low-dose end is expected. With increasing dose, saturation of DNA repair can introduce a sublinearity (example: dimethylnitrosamine). Stimulation of cell division as a result of high-dose toxicity and regenerative proliferation also results in a sublinear deviation from low-dose linearity. If the DNA-damaging potency of the carcinogen is low in comparison with the high-dose effects, the linear part of the low dose-cancer incidence curve might be hidden within the background variability. Under such conditions, 'practical thresholds' could be discussed (formaldehyde). If a carcinogen increases the rate of cell division or the level of oxidative stress at high dose but has an antimitogenic or antioxidative effect at low dose, a J-shaped (or: U-shaped) curve with a decrease of the spontaneous tumor incidence at low dose could result (caffeic acid; TCDD). This phenomenon has been observed even under conditions of a genotoxic contribution (ionizing radiation; diesel exhaust particles). For a mechanism-based assessment of a low-dose cancer risk, information on the various modes of action and modulations should be available over the full dose range, and models should be refined to incorporate the respective information.
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PMID:Dose-response relationships in chemical carcinogenesis: superposition of different mechanisms of action, resulting in linear-nonlinear curves, practical thresholds, J-shapes. 974 32

N-nitro-dimethylamine (NTDMA) is carcinogenic to rats: it induces nasal cavity tumours. It can be demethylated to N-nitromethylamine and formaldehyde and reduced to N-nitroso-dimethylamine (NDMA): a potent liver carcinogen and also of the nasal cavity if activation in the liver is blocked. To explain the mechanism of NTDMA carcinogenicity we compared its demethylation with that of NDMA in liver microsomes from female and male rats, untreated, fasted or treated with ethanol to induce cytochrome P450 2E1 (CYP2E1). Kinetic parameters were analysed by nonlinear statistical methods, which yielded unbiased parameter estimates for the calculated Km and Vmax values. Km for both compounds was very similar in females (24-47 microM) whereas Vmax for NTDMA was consistently higher than for NDMA as substrate: 1.07-4.70 nmol formaldehyde/mg microsomal protein x min and 0.52-2.76 nmol, respectively. In liver microsomes from induced male rats NTDMA was found to be a much more effective inhibitor of NDMA activation (KEI 39.6-73.6 microM) than NDMA of NTDMA demethylation (KEI 224-286 microM). Nasal microsomes can demethylate both NDMA and NTDMA but the kinetics are vastly different. NTDMA is demethylated at a linear rate and approximately 10-fold more effectively than NDMA. The mechanism of carcinogenicity of ingested NTDMA, we propose, is a partial reduction to NDMA in the liver and inhibition of NDMA activation in the liver by residual NTDMA, which enables NDMA to reach the nasal mucosa where it is activated to DNA-alkylating species and the observed tumours are formed.
Carcinogenesis 1999 Mar
PMID:Analysis of the inhibition of N-nitroso-dimethylamine activation in the liver by N-nitro-dimethylamine using a new non-linear statistical method. 1019 May 62

Human lymphoid cells (Raji) were exposed to water-soluble compounds from cigarette smoke (CS) generated in a smoking machine. DNA damage, as detected by alkaline single-cell microelectrophoresis (COMET assay), was induced in a time- and concentration-dependent manner in the cells. Most of the rapidly induced DNA damage was attributable to direct-acting compounds since cytochrome P450-related metabolic activities (ethoxy- and pentoxyresorufin-O-deethylases and coumarin-7-hydroxylase) were absent or very low. In addition, induction of DNA damage could be inhibited only slightly by beta-naphthoflavone and coumarin. Vitamin C enhanced DNA damage in Raji cells probably by redox cycling of catechol and hydroquinone present in CS implicating reactive oxygen intermediates as another source of DNA damage. N-acetylcysteine, a radical scavenger and glutathione precursor, reduced DNA damage in Raji cells when exposure to CS was followed by 2 h post-incubation in culture medium. Unrepaired DNA damage caused by CS persisted longer than gamma-irradiation-induced DNA damage. Among the CS constituents, acrolein, but not formaldehyde and acetaldehyde, induced DNA damage although less intensely than CS itself. At 50 and 100 microM concentrations, acrolein also inhibited repair of gamma- irradiation-induced DNA damage in the COMET assay. Inhibition of DNA synthesis by acrolein at 50 microM was demonstrated by an immunochemical assay for bromo-deoxyuridine incorporation; however, inhibition of a representative repair enzyme, 8-oxoguanosine hydrolase, by either CS or acrolein was not observed. The present results further confirm the presence of direct-acting genotoxic components and inhibitors of DNA repair in the gas phase of tobacco smoke, that may contribute to DNA damage and smoking-associated cancers of the upper aerodigestive tract.
Carcinogenesis 1999 Sep
PMID:Cigarette smoke induces direct DNA damage in the human B-lymphoid cell line Raji. 1046 23


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