8-oxo-7,8-dihydro-2'-deoxyguanosine as a biomarker of oxidative damage in oesophageal cancer patients: lack of association with antioxidant vitamins and polymorphism of hOGG1 and GST

International audienceThe present report was designed to investigate the origins of elevated oxidative stress measured in cancer patients in our previous work related to a case-control study (17 cases, 43 controls) on oesophageal cancers. The aim was to characterize the relationship between the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), antioxidant vitamins and genetic susceptibility

Ulcerative Colitis-Associated Colorectal Cancer Prevention by 5-Aminosalicylates: Current Status and Perspectives

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Benzo[a]pyrene, Aflatoxine B1 and Acetaldehyde Mutational Patterns in TP53 Gene Using a Functional Assay: Relevance to Human Cancer Aetiology

Mutations in the TP53 gene are the most common alterations in human tumours. TP53 mutational patterns have sometimes been linked to carcinogen exposure. In hepatocellular carcinoma, a specific G>T transversion on codon 249 is classically described as a fingerprint of aflatoxin B1 exposure. Likewise G>T transversions in codons 157 and 158 have been related to tobacco exposure in human lung cancers. However, controversies remain about the interpretation of TP53 mutational pattern in tumours as the fingerprint of genotoxin exposure. By using a functional assay, the Functional Analysis of Separated Alleles in Yeast (FASAY), the present study depicts the mutational pattern of TP53 in normal human fibroblasts after in vitro exposure to well-known carcinogens: benzo[a]pyrene, aflatoxin B1 and acetaldehyde. These in vitro patterns of mutations were then compared to those found in human tumours by using the IARC database of TP53 mutations. The results show that the TP53 mutational patterns found in human tumours can be only partly ascribed to genotoxin exposure. A complex interplay between the functional impact of the mutations on p53 phenotype and the cancer natural history may affect these patterns. However, our results strongly support that genotoxins exposure plays a major role in the aetiology of the considered cancers

Contribution à l'étude des mécanismes de l'interaction alcool-tabac dans l'étiologie du cancer de l'oesophage

The molecular basis of the interaction between alcohol in the aetiopathogenesis of esophageal squamous cell carcinoma remains unclear. One hypothesis is that alcohol intake could modify the expression of enzymes metabolizing tobacco carcinogens in liver and esophageal mucosa. First, we tested the hypothesis that different alcoholic beverages could differentially induce expression of liver and esophageal cytochromes P450 in rats treated by various alcohols (wine, cider, beer, whisky, calvados brandy-farm produced or commercial, ethanol alone) and then exposed to N-methylbenzylnitrosamine. The data show that induction of CYP2E1 with acute alcohol treatment was predominantly determined by the ethanol content of the beverage and that in rat this induction is seen in liver but not in esophagus. The type of beverage does not affect cyrochromes expression and methylation adducts in liver and esophagus. Second, from a study realized on biopsies of non neoplastic mucosa, we support the hypothesis that human oesophageal mucosa can activate different tobacco carcinogens. The presence of CYP2E1, CYP1A1/2 and CYP3A3/4 was confirmed in this tissu. We have related the level of their expression to epidemiological data concerning tobacco and alcohol consumption ; however no significant increase was seen. The cell proliferation could contribute to carcinogenesis process. The study of expression of cell proliferation marker (Ki67) and of p53 protein in non neoplastic mucosa near the tumor (12 cases) and normal mucosa (22) from healthy volunteers shows an important cell proliferation accompagnied with p53 expression in oesophagitis area. The appearance of chronic oesophagitis was related significantly to the level of hot alcohol brandies intake. These data suggest that carcinogenesis process could appear early in chronic inflammatory areas of esophageal mucosaLe mécanisme de l'interaction alcool-tabac dans l'étiologie du cancer épidermoïde de l'œsophage est mal connu. Une hypothèse serait que l'alcool modifierait l'expression des enzymes métabolisant les carcinogènes du tabac au niveau du foie et de l'œsophage. Nous avons mesuré dans un premier temps l'influence de différentes boissons alcoolisées (vin, cidre, bière whisky, calvados fermier ou industriel, éthanol seul) sur le métabolisme de certaines nitrosamines chez des rats traités de manière aiguë, puis exposé à la n-méthylbenzylnitrosamine. Une induction significative du cyp2e1 en rapport avec le taux d'éthanol a été observée dans des microsomes de foie, mais non dans des microsomes œsophagiens. Aucune influence de la nature de l'alcool consommé n'a été observée sur le taux d'adduits de méthylation et le niveau d'expression des cytochromes dans le foie et l'œsophage. Chez l'homme, notre première approche a été de confirmer la présence des p450 impliqués dans l'activation des carcinogènes du tabac dans des muqueuses œsophagiennes non néoplasiques et de rechercher une augmentation de l'expression en cas de consommation excessive d'alcool et de tabac. Les cyp1a1/2, 2e1 et 3a3/4 ont été détectés mais aucune relation significative n'a pu être mise en évidence entre le taux de protéines, le taux des transcrits et le nombre de cigarettes et de boissons alcoolisées. L'endommagement de la muqueuse œsophagienne à la suite d'une exposition directe aux boissons alcoolisées bues chaudes est susceptible d'induire une augmentation de la prolifération cellulaire qui pourrait contribuer au processus carcinogène. Nous avons montré par immunohistochimie, une prolifération accrue (ki67) dans les zones d'œsophagites chroniques accompagnée d'une surexpression de p53 dans des muqueuses œsophagiennes non néoplasiques adjacentes à la tumeur et normales prélevées respectivement chez des patients (12 cas) et des volontaires sains (22) résidant dans une région à haute incidence, la Basse-Normandie. Une relation significative a également été mise en évidence entre l'apparition d'œsophagite chronique et la consommation de calvados et d'autres digestifs bus chauds. L'ensemble de ces résultats suggèrent fortement l'apparition d'un processus prénéoplasique dans des zones de muqueuses œsophagiennes qui apparaissent histologiquement normale

Cancer Stem Cells of Head and Neck Squamous Cell Carcinoma

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Les cancers ORL (épidémiologie, traitements, dépistage et prévention)

CAEN-BU Médecine pharmacie (141182102) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Evaluation of Lung Cell Toxicity of Surfactants for Inhalation Route

International audienceFew data are available for excipients administered by inhalation route. This study evaluated the in vitro potential toxicity of three surfactants (Polysorbate 20, Polysorbate 80 and Poloxamer 188) by using an original air-liquid interface (ALI) method of exposure compared to liquid/liquid (L/L) model. Two cell toxicity tests were conducted on BEAS-2B cells, a human immortalized bronchial epithelial cell lines; measurement of Lactate Dehydrogenase activity and XTT cell proliferation assay. We found that Polysorbate 20 appeared to be more toxic than Polysorbate 80, Poloxamer 188. An increased toxicity of Polysorbate 20 in L/L system as shown in comparison to ALI exposure. A toxicity was also observed for polysorbate 80 but at higher concentrations and without difference between L/L and ALI exposure. No toxicity was observed for Poloxamer 188 at high concentrations.Poloxamer 188 seems to be the better candidate, out of the three tested, for galenic formulations designed to the inhalation route such as biotherapies. To evaluate the cytotoxicity of excipients for inhalation route the ALI exposure have to be used instead of L/L