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Carcinogenic Effects (carcinogenic + effects)
Selected AbstractsAppraising the mitogenicity of insulin analogues relative to human insulin,response to: Weinstein D, Simon M, Yehezkel E, Laron Z, Werner H. Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activity in cultured cancer cells.DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 3 2010Diabetes Metab Res Rev 2009; 25(1): 4 Abstract Interest in mitogenic and potentially carcinogenic effects of insulin and insulin analogues has been renewed by several recent publications that have examined the relationship between cancer and insulin analogues. Actions mediated through the insulin-like growth factor-I receptor in a hyperinsulinaemic state have been implicated mechanistically. Both type 2 diabetes and endogenously elevated insulin-like growth factor-I have been epidemiologically linked to malignancies. Therefore, in vitro mitogenic effects and binding affinities of the various analogues have been analysed. A recent publication by Weinstein et al. studied the in vitro mitogenic and anti-apoptotic activities of insulin analogues, and their conclusion asserts that insulins glargine, detemir, and lispro displayed proliferative and anti-apoptotic effects in a number of malignant cell lines. However, their conclusions are not supported by the data which are not complete and lack clear statistical significance. This data should be interpreted cautiously in light of all other presently available scientific evidence. Prospective, randomized clinical trials will best address any direct relationship between insulin analogues and cancer. Until those studies are designed and completed, clinicians should consider the demonstrated strong benefit of glycaemic control in balance with any alleged risk. Copyright © 2010 John Wiley & Sons, Ltd. [source] Environmental carcinogens and p53 tumor-suppressor gene interactions in a transgenic mouse model for mammary carcinogenesisENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2-3 2002Daniel Medina Abstract Mouse mammary tumorigenesis is greatly influenced by a variety of exogenous agents, such as MMTV, chemical carcinogens (i.e., polycyclic aromatic hydrocarbons), and radiation, as well as by endogenous/physiological factors, such as steroid hormones, tumor-suppressor genes (i.e., Brca1/2,p53), and gene products of modifier genes. In the mouse model, the most frequently used chemical carcinogen has been 7,12-dimethylbenz[a]anthracene (DMBA), which activates the Ha- ras gene but does not alter the p53 tumor-suppressor gene. However, on an existing background of p53 gene alteration, low doses of DMBA are strongly cocarcinogenic. Using a transgenic model system, in which the p53 gene was deleted in the mammary gland, we examined the carcinogenic effects of a variety of external agents and internal factors given at either low doses or physiological doses. These agents/factors included DMBA, ,-radiation, Brca2 heterozygosity, and steroid hormones. All agents/factors increased the tumorigenic response of the p53 null mammary cells, even under conditions where no tumorigenic response was observed in the p53 wildtype mammary cell. The strongest cocarcinogenic effect was observed with the steroid hormone progesterone. The majority of tumors were highly aneuploid and composed of nuclear igh-grade cells. The mechanism for the aneuploidy and secondary events associated with high tumorigenicity were examined using array technology. These results demonstrate that, on a background of underlying genetic instability, very low doses of environmental mutagens and mitogens can produce strong cocarcinogenic effects. Environ. Mol. Mutagen. 39:178,183, 2002. © 2002 Wiley-Liss, Inc. [source] Loss-of-function variants of the human melanocortin-1 receptor gene in melanoma cells define structural determinants of receptor functionFEBS JOURNAL, Issue 24 2002Jesús Sánchez Más The ,-melanocyte-stimulating hormone (,MSH) receptor (MC1R) is a major determinant of mammalian skin and hair pigmentation. Binding of ,MSH to MC1R in human melanocytes stimulates cell proliferation and synthesis of photoprotective eumelanin pigments. Certain MC1R alleles have been associated with increased risk of melanoma. This can be theoretically considered on two grounds. First, gain-of-function mutations may stimulate proliferation, thus promoting dysplastic lesions. Second, and opposite, loss-of-function mutations may decrease eumelanin contents, and impair protection against the carcinogenic effects of UV light, thus predisposing to skin cancers. To test these possibilities, we sequenced the MC1R gene from seven human melanoma cell (HMC) lines and three giant congenital nevus cell (GCNC) cultures. Four HMC lines and two GCNC cultures contained MC1R allelic variants. These were the known loss-of-function Arg142His and Arg151Cys alleles and a new variant, Leu93Arg. Moreover, impaired response to a superpotent ,MSH analog was demonstrated for the cell line carrying the Leu93Arg allele and for a HMC line homozygous for wild-type MC1R. Functional analysis in heterologous cells stably or transiently expressing this variant demonstrated that Leu93Arg is a loss-of-function mutation abolishing agonist binding. These results, together with site-directed mutagenesis of the vicinal Glu94, demonstrate that the MC1R second transmembrane fragment is critical for agonist binding and maintenance of a resting conformation, whereas the second intracellular loop is essential for coupling to the cAMP system. Therefore, loss-of-function, but not activating MC1R mutations are common in HMC. Their study provides important clues to understand MC1R structure-function relationships. [source] Interaction between hepatitis B and C viruses in hepatocellular carcinogenesisJOURNAL OF VIRAL HEPATITIS, Issue 3 2006M. C. Kew Summary., Although hepatitis B (HBV) and C viruses (HCV) are, individually, major causes of hepatocellular carcinoma, the interaction, if any, between the carcinogenic effects of the two viruses is uncertain. Equal numbers of published studies have reported no risk interaction or a synergistic risk interaction. These conflicting results are explained by the rarity of concurrent infection with HBV and HCV in individuals without clinically evident liver disease, which severely limits the ability to accurately estimate the hepatocarcinogenic risk of dual infection compared with that of either infection alone. In an attempt to circumvent this difficulty, two meta-analyses have been performed, one based on studies published from a number of countries and the other on studies confined to Chinese patients. Both analyses concluded that a synergistic carcinogenic interaction existed between the two viruses and that the increased risk was super-additive but not multiplicative. If confirmed, this risk interaction will occur against a background of negative confounding effects on viral replication between HBV and HCV, which may be reciprocal. The mechanisms responsible for the carcinogenic interaction between the viruses are unknown. One possibility is that the increased incidence of cirrhosis with concurrent HBV and HCV infections acts as an even more potent tumour promoter than occurs with either virus alone. Synergism between the direct hepatocarcinogenic effects of the two viruses is another possible mechanism, but proof will have to await a fuller understanding of the pathogenetic mechanisms involved with the individual viruses. [source] Inositol hexaphosphate inhibits ultraviolet B,induced signal transductionMOLECULAR CARCINOGENESIS, Issue 3 2001Nanyue Chen Abstract Inositol hexaphosphate (InsP6) has an effective anticancer action in many experimental models in vivo and in vitro. Ultraviolet B (UVB) radiation is believed to be responsible for many of the carcinogenic effects related to sun exposure, and alteration in UVB-induced signal transduction is associated with UVB-induced carcinogenesis. Here we report the effects of InsP6 on UVB-induced signal transduction. InsP6 strongly blocked UVB-induced activator protein-1 (AP-1) and NF-,B transcriptional activities in a dose-dependent manner. InsP6 also suppressed UVB-induced AP-1 and nuclear factor ,B (NF-,B) DNA binding activities and inhibited UVB-induced phosphorylation of extracellular signal-regulated protein kinases (Erks) and c-Jun NH2-terminal kinases (JNKs). Phosphorylation of p38 kinases was not affected. InsP6 also blocked UVB-induced phosphorylation of I,B-,, which is known to result in the inhibition of NF-,B transcriptional activity. InsP6 does not block UVB-induced phosphotidylinositol-3, (PI-3) kinase activity, suggesting that the inhibition of UVB-induced AP-1 and NF-,B activities by InsP6 is not mediated through PI-3 kinase. Because AP-1 and NF-,B are important nuclear transcription factors that are related to tumor promotion, our work suggests that InsP6 prevents UVB-induced carcinogenesis by inhibiting AP-1 and NF-,B transcription activities. © 2001 Wiley-Liss, Inc. [source] Risk of second malignant neoplasms among childhood cancer survivors treated with radiotherapy: meta-analysis of nine epidemiological studiesPAEDIATRIC & PERINATAL EPIDEMIOLOGY, Issue 4 2009Kazutaka Doi Summary In the light of notable advances made in childhood cancer therapies, an understanding of the late effects of treatment is important for continued medical care. We conducted a meta-analysis of studies on the excess relative risk (ERR) of second malignant neoplasm (SMN) among childhood cancer survivors treated with radiotherapy. Relevant studies were retrieved by searching the PubMed database, supplemented by hand-searching of reference lists of already retrieved papers. Nine studies were identified and overall ERR estimates were calculated using a fixed effects model and a random effects model. The overall ERR per Gy (absorbed dose of ionising radiation) estimates of radiotherapy by a fixed effect model and a random effects model were 0.50 [95% CI 0.20, 1.21] and 0.53 [95% CI 0.22, 1.31] respectively. Heterogeneity among studies was suggested by Cochran's Q statistic (Q = 40.4, d.f. = 8, P < 0.001). The estimate obtained using a random effects model was far smaller than the corresponding estimate of 1.7 [95% CI 1.1, 2.5] from the study on atomic bomb survivors exposed as young children, suggesting underestimation of ERR estimates among the nine studies compared with the estimates from the study of atomic bomb survivors. In view of the heterogeneity and underestimation in ERR estimates, more studies concerning the risk of SMN among childhood cancer survivors are still needed for further understanding of the carcinogenic effects of radiotherapy on children. [source] Aberrant methylation and loss of expression of O6 -methylguanine-DNA methyltransferase in pulmonary squamous cell carcinoma and adenocarcinomaPATHOLOGY INTERNATIONAL, Issue 6 2005Osamu Furonaka O6 -Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that protects cells against the carcinogenic effects of alkylating agents. The methylation status of the MGMT gene was investigated by methylation-specific polymerase chain reaction (PCR) and expression status was investigated by immunohistochemistry in 70 cases of pulmonary squamous cell carcinoma (pulmonary SqCC), including 23 cases of the central type and 47 cases of the peripheral type, and in 53 cases of the peripheral type of pulmonary adenocarcinoma (AC). The frequency of MGMT methylation was 36% in SqCC and 42% in AC. Cases with MGMT methylation correlated significantly with T factor in SqCC (P = 0.047) and AC (P = 0.03). In SqCC, the frequency of MGMT methylation was 26% in the central type and 40% in the peripheral type; a significant correlation was not found (P = 0.29). In AC with mixed subtypes showing MGMT methylation, the level of MGMT expression in the bronchioloalveolar carcinoma (BAC) area (non-invasive status) was significantly higher than that in the papillary or acinar AC area (invasive status; P = 0.0002). This trend was not found in AC with mixed subtypes showing no MGMT methylation (P = 0.10). These findings suggest that MGMT inactivation is an event that occurs in the late carcinogenic process in SqCC and AC, and that AC progress from non-invasive status to invasive status with MGMT inactivation induced by the promoter DNA methylation. [source] Public safety aspects of pyrethroid insecticides used in West Nile virus-carrying mosquito control,PEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 7 2007Derek W Gammon Abstract West Nile virus is becoming increasingly prevalent in the USA, causing fever, encephalitis, meningitis and many fatalities. Spread of the disease is reduced by controlling the mosquito vectors by a variety of means, including the use of pyrethroid insecticides, which are currently under scrutiny for potential carcinogenic effects in humans. Pyrethrins and resmethrin, a pyrethroid, have been shown to cause tumours in rat and mouse models respectively. However, the tumours appear to be caused by liver enzyme induction and hypertrophy rather than genotoxicity, and the results are therefore unlikely to be applicable to humans. Nonetheless, for resmethrin, the US Environmental Protection Agency (EPA) has concluded that there is a likely risk of carcinogenicity in humans, requiring the manufacturers to provide more detailed data to prove that it can be used safely in vector control. Reproductive toxicity of resmethrin in the rat is also discussed. Copyright © 2007 Society of Chemical Industry [source] Ultraviolet A exposure might increase metastasis of mouse melanoma: a pilot studyPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 4 2005Riikka Pastila Background: The major sources of long-wave ultraviolet A radiation (UVA; 320,400 nm) exposure are extensive sunbathing and tanning in solaria. While the carcinogenic effects of mid-wave ultraviolet B radiation (UVB; 280,320 nm) are well recognized, the potentially hazardous effects of UVA are less understood. Several studies have shown that a variety of physiological processes in the cell are modified by UVA exposure, some of which might be involved in the regulation of tumor metastasis. In this study we suggest that UVA radiation could lead to the increase of metastatic capability of melanoma cells in mice. Method/result: A pilot in vivo study was executed using C57BL/6 mice and syngeneic B16 melanoma cell lines. Mice were intravenously (i.v.) injected with either B16-F1 or B16-F10 melanoma cells into the tail vein and then immediately exposed to UVA. Fourteen days after melanoma injection, lungs were collected and the quantity and quality of metastases were determined under a dissecting microscope. As an outcome of the pilot study we observed that i.v. injected melanoma cells formed more lung metastases in the UVA-exposed mice in comparison with the control mice. Conclusion: This result suggests that the UVA exposure of mice, with melanoma cells present in blood circulation, increases the formation of melanoma metastases in lungs. Further studies should determine whether a similar pro-metastatic effect, as observed in mice, could occur in humans and whether other than melanoma tumors might be susceptible. [source] Lung cancer risk associated with occupational exposure to nickel, chromium VI, and cadmium in two population-based case,control studies in MontrealAMERICAN JOURNAL OF INDUSTRIAL MEDICINE, Issue 5 2010Rachelle Beveridge MSc Abstract Background Nickel, chromium VI, and cadmium have been identified as lung carcinogens in highly exposed cohorts. The purpose of this study was to examine the etiological link between lung cancer and these metals in occupations, that usually entail lower levels of exposure than those seen in historical cohorts. Methods Two population-based case,control studies were conducted in Montreal, from 1979 to 1986 and from 1996 to 2001, comprising 1,598 cases and 1,965 controls. A detailed job history was obtained to evaluate lifetime occupational exposure to many agents, including nickel, chromium VI, and cadmium compounds. Results Lung cancer odds ratios were increased only among former or non-smokers: 2.5 (95% CI: 1.3,4.7) for nickel exposure, 2.4 (95% CI: 1.2,4.8) for chromium VI, and 4.7 (95% CI: 1.5,14.3) for cadmium. The metals did not increase risk among smokers. Conclusions While excess risks due to these metal compounds were barely discernable among smokers, carcinogenic effects were seen among non-smokers. Am. J. Ind. Med. 53:476,485, 2010. © 2010 Wiley-Liss, Inc. [source] Differential adduction of proteins vs. deoxynucleosides by methyl methanesulfonate and 1-methyl-1-nitrosourea in vitro,RAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 4 2005Fagen Zhang The reactions of two model mutagenic and carcinogenic alkylating agents, N -methyl- N -nitrosourea (MNU) and methyl methanesulfonate (MMS), with proteins and deoxynucleosides in vitro, were investigated. The protein work used an approach involving trypsin digestion and high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ESI-MS/MS). This technique permitted identification of the specific location of protein adduction by both MNU and MMS with commercial apomyoglobin and human hemoglobin, under physiological conditions. MNU treatment resulted in predominantly carbamoylation adducts on the proteins, but in contrast only methylated protein adducts were found following treatment with MMS. Further analyses, using TurboSequest®, and the Scoring Algorithm for Spectral Analysis (SALSA), revealed that MNU carbamoylation was specific for modification of either the N-terminal valine or the free amino group in lysine residues of apomyglobin and human hemoglobin. However, MMS methylation modified the N-terminal valine and histidine residues of the proteins. Despite their clear differences in protein modifications, MNU and MMS formed qualitatively the same methylated deoxynucleoside adduct profiles with all four deoxynucleosides in vitro under physiological conditions. In light of their different biological potencies, where MMS is considered a ,super clastogen' while MNU is a ,super mutagen', these differences in reaction products with proteins vs. deoxynucleosides may indicate that these two model alkylating agents work via different mechanisms to produce their mutagenic and carcinogenic effects. Copyright © 2005 John Wiley & Sons, Ltd. [source] Mobile phone use and location of glioma: A case,case analysisBIOELECTROMAGNETICS, Issue 3 2009Hanna Hartikka Abstract We assessed a new approach for evaluating the glioma risk among users of mobile phones to focus on the part of the brain most heavily exposed to radiofrequency electromagnetic fields from mobile phones. The tumor midpoint was defined from radiological imaging. A case,case analysis with 99 gliomas was performed using logistic regression. The exposed cases were those with the tumor mid-point within 4.6 cm from the line between the mouth and the external meatus of the ear, representing the most likely location of the mobile phone (the source of exposure). Alternative analyses based on various indicators of mobile phone use as the outcome were also carried out. The majority of cases were regular mobile phone users. A slightly higher proportion of gliomas among mobile phone users than non-users occurred within 4.6 cm from the presumed location of the mobile phone (28% vs. 14%). Modestly elevated odds ratios were observed for several indicators of mobile phone use, but without an exposure gradient. The highest odds ratios were found for contralateral and short-term use. Our results, though limited by the small sample size, demonstrate that detailed information on tumor location allows evaluation of the risk related to the most heavily exposed part of the brain, representing direct evaluation of the possible local carcinogenic effects of the radiofrequency fields. However, field strength varies between users and over time also within a given anatomic site, due to the output power of the phone. Collaborative analysis of a larger sample is planned. Bioelectromagnetics 30:176,182, 2009. © 2009 Wiley-Liss, Inc. [source] Carcinogenicity study of GSM and DCS wireless communication signals in B6C3F1 miceBIOELECTROMAGNETICS, Issue 3 2007Thomas Tillmann Abstract The purpose of this study using a total of 1170 B6C3F1 mice was to detect and evaluate possible carcinogenic effects in mice exposed to radio-frequency-radiation (RFR) from Global System for Mobile Communication (GSM) and Digital Personal Communications System (DCS) handsets as emitted by handsets operating in the center of the communication band, that is, at 902 MHz (GSM) and 1747 MHz (DCS). Restrained mice were exposed for 2 h per day, 5 days per week over a period of 2 years to three different whole-body averaged specific absorption rate (SAR) levels of 0.4, 1.3, 4.0 mW/g bw (SAR), or were sham exposed. Regarding the organ-related tumor incidence, pairwise Fisher's test did not show any significant increase in the incidence of any particular tumor type in the RF exposed groups as compared to the sham exposed group. Interestingly, while the incidences of hepatocellular carcinomas were similar in EMF and sham exposed groups, in both studies the incidences of liver adenomas in males decreased with increasing dose levels; the incidences in the high dose groups were statistically significantly different from those in the sham exposed groups. Comparison to published tumor rates in untreated mice revealed that the observed tumor rates were within the range of historical control data. In conclusion, the present study produced no evidence that the exposure of male and female B6C3F1 mice to wireless GSM and DCS radio frequency signals at a whole body absorption rate of up to 4.0 W/kg resulted in any adverse health effect or had any cumulative influence on the incidence or severity of neoplastic and non-neoplastic background lesions, and thus the study did not provide any evidence of RF possessing a carcinogenic potential. Bioelectromagnetics 28:173,187, 2007. © 2006 Wiley-Liss, Inc. [source] The effect of vitamin E on acute skin reaction caused by radiotherapyCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 5 2007A. Dirier Summary Ionizing radiation affects healthy organs and tissues as well as diseased tissues during radiation therapy. Skin reactions varying from acute erythema to necrosis can be seen. It has been found that vitamin E can prevent mutagenic and/or carcinogenic effects of ionizing radiation in both animals and cell cultures. This study investigated the preventative effect of antioxidant vitamin E on irradiation-induced acute skin reactions. No protective effect of vitamin E was demonstrated. It is possible that the vehicle induced free radical exposure in the irradiated skin. [source] | ||||||||||||||||