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Dendritic cells (DCs) are the most potent antigenpresenting cells and acquire cellular antigens and danger signals from dying cells to initiate antitumor immune responses via direct cell-to-cell interaction and cytokine production. The optimal forms of tumor cell death for priming DCs for the release of danger signals are not fully understood. OBP-301 (Telomelysin) is a telomerasespecific replication-competent adenovirus that induces selective E1 expression and exclusively kills human cancer cells. Here, we show that OBP-301 replication produced the endogenous danger signaling molecule, uric acid, in infected human tumor cells, which in turn stimulated DCs to produce interferon-c (IFN-c) and interleukin 12 (IL-12). Subsequently, IFN-c release upregulated the endogenous expression of the proteasome activator PA28 in tumor cells and resulted in the induction of cytotoxic T-lymphocytes. Our data suggest that virus-mediated oncolysis might be the effective stimulus for immature DCs to induce specific activity against human cancer cells.

Oncolytic adenoviruses are being developed as novel anticancer therapeutics and currently undergoing clinical trials. We previously demonstrated that telomerase-specific replication-competent adenovirus (Telomelysin: OBP-301), in which the human telomer-ase reverse transcriptase (hTERT) promoter regulates viral repli-cation, efficiently killed human tumor cells. We further constructed OBP-401 (Telomelysin-GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region to monitor viral distribution. Here, we examined the feasibility of a single-agent therapy with OBP-401 as well as of combining OBP-401 with chemothera-peutic agents. Infection of OBP-401 alone or followed by the treatment of a chemotherapeutic drug, docetaxel (Taxotere), resulted in a profound in vitro cytotoxicity and GFP expression in various human cancer cell lines originating from different organs (lung, colon, esophagus, stomach, liver and prostate), although the magnitude of antitumor effect varied among the cell types. Other che-motherapeutic drugs such as vinorelbine (Navelbine) and SN38 (the potent active metabolite of irinotecan) combined with OBP-401 also inhibited the growth of human cancer cells. Quantitative real-time PCR analysis demonstrated that docetaxel did not affect viral replication. For in vivo evaluation, nu/nu mice xenografted with H1299 human lung tumor received intratumoral injection of OBP-401 and intraperitoneal administration of docetaxel. Analysis of growth of implanted tumors showed a significant, therapeutic synergism, although OBP-401 alone and docetaxel alone showed modest inhibition of tumor growth. Thus, OBP-401 in combination with docetaxel efficiently enhances the antitumor efficacy both in vitro and in vivo, and the outcome has important implications for tumor-specific oncolytic chemovirotherapies for human cancers. ' 2006 Wiley-Liss, Inc. Lack of restricted selectivity for tumor cells is the primary limitation of common cancer therapeutics such as chemotherapy and radiotherapy. To improve the therapeutic index, there is a need for anticancer agents that selectively target only tumor cells and spare normal cells. Telomerase is a ribonucleoprotein complex responsible for the complete replication of chromosomal ends. 1 Many studies have demonstrated the expression of telomerase activity in more than 85% of human cancers, 2 but only in few normal somatic cells. 3 Telomerase activation is considered a critical step in carci-nogenesis and its activity is closely correlated with human telo-merase reverse transcriptase (hTERT) expression. 4 Replication-selective tumor-specific adenoviruses are being developed as novel anticancer therapies. 5-9 We previously developed an adeno-virus vector that drives E1A and E1B genes under the hTERT promoter , namely Telomelysin: OBP-301, 10-12 and showed its selective replication as well as profound cytotoxic activity in a variety of human cancer cells. Although the development of OBP-301 as a monotherapy is...

Background: Recent studies indicated that periodontitis induces systemic low‐grade inflammation. The increase in systemic low‐grade inflammation induced by periodontitis may alter the effects of obesity on the production of inflammatory molecules, including C‐reactive protein (CRP), interleukin (IL)‐6, and tumor necrosis factor‐alpha (TNF‐α), in the liver and white adipose tissue (WAT). The purpose of the present study is to investigate the effects of periodontitis on the expression of proinflammatory cytokines in the liver and WAT in obese Zucker rats. Methods: Obese Zucker rats and their lean litter mates were divided into four groups of six rats each: lean Zucker rats without periodontitis (control group), lean Zucker rats with periodontitis (periodontitis group), obese Zucker rats without periodontitis (obesity group), and obese Zucker rats with periodontitis (combination group). Periodontitis was ligature induced for 4 weeks in the periodontitis and combination groups, whereas the other groups were left unligated. Results: At 4 weeks, the gene expression for CRP, IL‐6, and TNF‐α in the liver and CRP and IL‐6 in the WAT of combination groups was significantly higher than in each of the three groups. Serum TNF‐α in the periodontitis and obesity groups was significantly higher than in the control group. Serum CRP and TNF‐α in the combination group was significantly higher than in each of the three groups. Conclusion: Systemic low‐grade inflammation after experimental periodontitis was associated with increased gene expression for hepatic levels of TNF‐α and CRP and adipose tissue levels of IL‐6 and CRP in the obese‐rat model.