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Articles by J Fujimoto
Total Records ( 2 ) for J Fujimoto
  J Deng , J Fujimoto , X. F Ye , T. Y Men , C. S Van Pelt , Y. L Chen , X. F Lin , H Kadara , Q Tao , D Lotan and R. Lotan
 

Mouse models can be useful for increasing the understanding of lung tumorigenesis and assessing the potential of chemopreventive agents. We explored the role of inflammation in lung tumor development in mice with knockout of the tumor suppressor Gprc5a. Examination of normal lung tissue and tumors from 51 Gprc5a+/+ (adenoma incidence, 9.8%; adenocarcinoma, 0%) and 38 Gprc5a–/– mice (adenoma, 63%; adenocarcinoma, 21%) revealed macrophage infiltration into lungs of 45% of the Gprc5a–/– mice and 8% of Gprc5a+/+ mice and the direct association of macrophages with 42% of adenomas and 88% of adenocarcinomas in the knockout mice. Gprc5a–/– mouse lungs contained higher constitutive levels of proinflammatory cytokines and chemokines and were more sensitive than lungs of Gprc5a+/+ mice to stimulation of NF-B activation by lipopolysaccharide in vivo. Studies with epithelial cells cultured from tracheas of Gprc5a–/– and Gprc5a+/+ mice revealed that Gprc5a loss is associated with increased cell proliferation, resistance to cell death in suspension, and increased basal, tumor necrosis factor –induced, and lipopolysaccharide-induced NF-B activation, which were reversed partially in Gprc5a–/– adenocarcinoma cells by reexpression of Gprc5a. Compared with Gprc5a+/+ cells, the Gprc5a–/– cells produced higher levels of chemokines and cytokines and their conditioned medium induced more extensive macrophage migration. Silencing Gprc5a and the p65 subunit of NF-B in Gprc5a+/+ and Gprc5a–/– cells, respectively, reversed these effects. Thus, Gprc5a loss enhances NF-B activation in lung epithelial cells, leading to increased autocrine and paracrine interactions, cell autonomy, and enhanced inflammation, which may synergize in the creation of a tumor-promoting microenvironment. Cancer Prev Res; 3(4); 424–37. ©2010 AACR.

  J Fujimoto , M Kong , J. J Lee , W. K Hong and R. Lotan
 

Lung cancer is the leading cause of cancer death, developing over prolonged periods through genetic and epigenetic changes induced and exacerbated by tobacco exposure. Many epigenetic changes, including DNA methylation and histone methylation and acetylation, are reversible. The use of agents that can modulate these aberrations are a potentially effective approach to cancer chemoprevention. Combined epigenetic-targeting agents have gained interest for their potential to increase efficacy and lower toxicity. The present study applied recently developed statistical methods to validate the combined effects of the demethylating agent 5-aza-2-deoxycytidine (5-AZA-CdR, or AZA, or decitabine) and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA or vorinostat). This validation compared AZA alone with SAHA alone and with their combinations (at later or earlier time points and in varying doses) for inhibiting the growth of cell lines of an in vitro lung carcinogenesis system. This system comprises isogenic premalignant and malignant cells that are immortalized (earlier premalignant), transformed (later premalignant), and tumorigenic human bronchial epithelial cells [immortalized BEAS-2B and its derivatives 1799 (immortalized), 1198 (transformed), and 1170-I (tumorigenic)]. AZA alone and SAHA alone produced a limited (<50%) inhibition of cell growth, whereas combined AZA and SAHA inhibited cell growth more than either agent alone, reaching 90% inhibition under some conditions. Results of drug interaction analyses in the Emax model and semiparametric model supported the conclusion that drug combinations exert synergistic effects (i.e., beyond additivity in the Loewe model). The present results show the applicability of our novel statistical methodology for quantitatively assessing drug synergy across a wide range of doses of agents with complex dose-response profiles, a methodology with great potential for advancing the development of chemopreventive combinations. Cancer Prev Res; 3(8); 917–28. ©2010 AACR.

 
 
 
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