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Aryl hydrocarbons such as 3-nitrobenzanthrone (NBA), 4-aminobiphenyl (ABP), acetylaminofluorene (AAF), benzo(a)pyrene (BaP), and 1-nitropyrene (NP) form bulky DNA adducts when absorbed by mammalian cells. These chemicals are metabolically activated to reactive forms in mammalian cells and preferentially get attached covalently to the N2 or C8 positions of guanine or the N6 position of adenine. The proportion of N2 and C8 guanine adducts in DNA differs among chemicals. Although these adducts block DNA replication, cells have a mechanism allowing to continue replication by bypassing these adducts: translesion DNA synthesis (TLS). TLS is performed by translesion DNA polymerases-Pol η, κ, ι, and ζ and Rev1-in an error-free or error-prone manner. Regarding the NBA adducts, namely, 2-(2'-deoxyguanosin-N2-yl)-3-aminobenzanthrone (dG-N2-ABA) and N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone (dG-C8-ABA), dG-N2-ABA is produced more often than dG-C8-ABA, whereas dG-C8-ABA blocks DNA replication more strongly than dG-N2-ABA. dG-N2-ABA allows for a less error-prone bypass than dG-C8-ABA does. Pol η and κ are stronger contributors to TLS over dG-C8-ABA, and Pol κ bypasses dG-C8-ABA in an error-prone manner. TLS efficiency and error-proneness are affected by the sequences surrounding the adduct, as demonstrated in our previous study on an ABP adduct, N-(2'-deoxyguanosine-8-yl)-4-aminobiphenyl (dG-C8-ABP). Elucidation of the general mechanisms determining efficiency, error-proneness, and the polymerases involved in TLS over various adducts is the next step in the research on TLS. These TLS studies will clarify the mechanisms underlying aryl hydrocarbon mutagenesis and carcinogenesis in more detail.

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DNA mutations play a crucial role in the origins of cancer, and the clonal expansion of mutant cells is one of the fundamental steps in multistage carcinogenesis. In this study, we correlated tumor incidence in B6C3F1 mice during the period after exposure to N-ethyl-N-nitrosourea (ENU) with the persistence of ENU-induced mutant clones in transgenic gpt delta B6C3F1 mice. The induced gpt mutations afforded no selective advantage in the mouse cells and could be distinguished by a mutational spectrum that is characteristic of ENU treatment. The gpt mutations were passengers of the mutant cell of origin and its daughter cells and thus could be used as neutral markers of clones that arose and persisted in the tissues. Female B6C3F1 mice exposed for 1 month to 200 ppm ENU in the drinking water developed early thymic lymphomas and late liver and lung tumors. To assay gpt mutations, we sampled the thymus, liver, lung, and small intestine of female gpt delta mice at 3 days, 4 weeks, and 8 weeks after the end of ENU exposure. Our results reveal that, in all four tissues, the ENU-induced gpt mutations persisted for weeks after the end of mutagen exposure. Clonal expansion of mutant cells was observed in the thymus and small intestine, with the thymus showing larger clone sizes. These results indicate that the clearance of mutant cells and the potential for clonal expansion during normal tissue growth depends on tissue type and that these factors may affect the sensitivity of different tissues to carcinogenesis. Environ. Mol. Mutagen. 58:592-606, 2017. © 2017 Wiley Periodicals, Inc.

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PURPOSE: The aim of this study was to evaluate the enhancement behavior of pancreatic ductal carcinoma by contrast-enhanced sonography with agent detection imaging (ADI), and to clarify the origin of microbubble signals by comparisons with histological findings of resected specimens. METHODS: The subjects were 21 patients with resectable pancreatic carcinoma. The final histological diagnosis was tubular adenocarcinoma in 20 cases, and anaplastic carcinoma in one case. Ultrasound examinations were performed using an Acuson Sequoia 512 series system, and the contrast agent (Levovist) was injected intravenously in doses of 7 ml (300 mg/ml). The ADI signals (in the tumor) were recorded continuously for 30 s after an injection of Levovist (vascular image) and then obtained intermittently (30 s time-intervals) until the signal had diminished in pancreatic tissue (perfusion image). RESULTS: Contrast enhancement of the tumor was observed in 71.4% of subjects on the vascular image and 76.3% of subjects on the perfusion image. Enhancement patterns on the vascular image were classified into three types: VI-1 (linear enhancement), VI-2 (spotty enhancement), and VI-3 (no enhancement). VI-1, VI-2, and VI-3 were seen in 9 (42.8%), 6 (28.6%), and 6 (28.6%) of the 21 cases, respectively. Enhancement patterns on the perfusion image were classified into four types: PI-1 (diffuse uneven enhancement), PI-2 (spotty enhancement), PI-3 (peripheral enhancement), and PI-4 (negative enhancement). The incidence of PI-1, PI-2, PI-3, and PI-4 was 4.8%, 42.9%, 28.6%, and 23.8%, respectively. With respect to resectable cases, these enhancement patterns were compared with histological findings, i.e., the distribution of blood vessels in the tumor, remaining pancreatic tissues in the tumor, differentiation of types of adenocarcinoma, volume of stroma, and invasion types of carcinoma. The enhanced patterns consequently corresponded to either the distribution of the blood vessels or the remaining pancreatic tissues in the tumor. CONCLUSION: This study indicated that pancreatic ductal carcinoma is frequently enhanced by microbubbles, and the signals seem to originate from fine blood vessels and the remaining pancreatic tissues in the tumor.

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Thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) are important enzymes in the pyrimidine salvage pathway. In the meantime, TP and DPD are a converting enzyme of 5'-DFUR to 5-FU and the major catabolic enzyme of 5-FU, respectively. Because little is known about their protein expressions in ovarian cancers, we investigated TP and DPD protein expressions quantitatively in 24 ovarian cancers and their normal counterparts by ELISA. Higher TP expression was observed in ovarian cancers than in normal ovaries. The higher expression was also correlated with the histological grade and clinical stage. No relation was observed between the expression of DPD and the clinical and pathological parameters. The higher TP/DPD ratio, which appears to be a predictor of 5-fluorouracil sensitivity, was observed in ovarian cancers than in normal counterparts. In univariate analysis, a higher TP/DPD ratio was found to be a predictor of progression-free survival in ovarian cancer patients. This would suggest that capecitabine and 5'-DFUR are potential candidates for ovarian cancer chemotherapy.

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