IL-21 supports proliferation of mature T and B cells and facilitates expansion and maturation of natural killer (NK) cells in synergy with IL-15. However, the biological implications of IL-21 in vivo have not been fully elucidated. IL-21 and IL-15 expression plasmids were intravenously injected under high pressure into the tail veins of mice, which were subsequently challenged by an intravenous injection of RLmale1 lymphoma cells. The IL15 gene transfection significantly reduced the numbers of metastatic tumor foci in the liver. In contrast, when IL21 and IL15 genes were cotransfected, complete regression was achieved in 80% of the mice. The cytokine gene therapy was also performed in mice that had been intravenously inoculated with the tumor cells. Forty percent of mice that received a single injection of a mixture of cytokine genes successfully rejected the preestablished metastatic lymphoma and showed tumor-free survival for more than 300 days. IL-21 significantly elevated the cytotoxic T lymphocyte activity in the spleens of tumor-inoculated mice, while the two cytokines augmented NK killing activity in a synergistic manner. These results strongly suggest that the codelivery of IL-21 and IL-15 elicits powerful antitumor immune responses, resulting in marked therapeutic efficacy against metastatic tumors.

To treat established melanoma in mice, intratumoral transfer of bleomycin and/or an interleukin (IL)-12 expression vector was performed by means of electroporation. Although either bleomycin alone or the IL12 gene alone significantly suppressed the subcutaneous tumors, the combination therapy drastically improved the therapeutic outcome. Three of eight mice (37.5%) that received both bleomycin and the IL12 gene showed complete remission of the preestablished tumors and rejected subsequent rechallenge with the tumor cells. We also examined whether electrochemo-gene therapy for subcutaneous tumor mass induced suppression of pulmonary metastasis that had been established by intravenous inoculation of the melanoma cells. Although metastatic foci were significantly reduced in number in groups that were given IL12 gene alone or bleomycin plus IL12 gene, it was only the combination therapy that significantly prolonged the mean survival period of the tumor-bearing animals. Natural killer (NK) and cytotoxic T lymphocyte cytolytic activities were markedly enhanced in the mice that received the chemo-gene therapy, while IL12 gene therapy alone partially elevated the NK cytotoxicity. The present study suggests that the electroporation-mediated delivery of the IL12 gene and bleomycin synergistically elicits innate and adaptive anti-melanoma immune responses, resulting in marked suppression of the treated tumors as well as bystander metastatic lesions.

Naked plasmid DNA (pDNA) vaccine expressing herpes simplex virus type 1 (HSV-1) glycoprotein B (gB) was tested for protective activity against acute HSV-1 infection in mice. The pDNA was intravenously injected into Balb/c mice via their tail vein under high pressure, and the vaccination was performed two times at an interval of 7 days. The gB gene vaccination significantly protected the mice from subsequent intraperitoneal challenge with a lethal dose of HSV-1, which killed all the animals given control plasmid or saline. The protective activity was correlated with the dose of the plasmid inoculated, the survival rate reaching 83% in mice vaccinated with 5 mg of pDNA. The vaccinated mice were also protected from latent HSV infection. The immunized mice showed significant elevation in neutralizing antibody against HSV-1 as well as serum levels of interleukin-12 (IL-12) and interferon-g (IFN-g). When mice were immunized with 5 mg of an Epstein-Barr virus (EBV)-based plasmid vector harboring the gB, the cytotoxic T lymphocytes (CTLs) activity and proliferative response for HSV-1 were also induced. The results strongly suggest that intravenous immunization of naked pDNA may induce humoral and cellular immune responses against the virus, leading to a significant prophylactic outcome against HSV-1 infection in mice.

prognosis of advanced gastric cancer is still poor, chemotherapies were reported to improve the overall survival compared to the best supportive care in several studies [2][3][4]. Among the various active chemotherapeutic agents, cisplatin-based chemotherapy is the most commonly used worldwide. The V-325 study demonstrated that adding docetaxel (D) to a frequently used regimen of cisplatin and 5-fl uorouracil (CF) provided benefi ts with regard to overall survival, response rate, time to disease progression, clinical benefi t, and healthrelated quality of life [5]. Although the DCF regimen provides these advantages, it is accompanied by an increase in toxicity compared with the doublet regimen. The toxicity profi le of DCF is acceptable only with appropriately selected patients and comprehensive toxicity management strategies [6]. In this regard, the development of less toxic new combination chemotherapy has still been considered necessary to properly treat those patients with advanced gastric cancer.Paclitaxel, (Taxol; Bristol-Myers Squibb, Princeton, NJ, USA), which is derived from the bark of the Pacifi c yew, Taxus brevifolia, is one of the most active anticancer drugs for the treatment of solid tumors, effectively blocking cancer cells in the G2/M phase through the inhibition of microtubular depolymerization [7,8]. An administration schedule at doses of 175-225 mg/m 2 by intravenous infusion every 3 weeks has been widely accepted [9]. In addition, several phase II studies have shown that paclitaxel, alone or in combination with cisplatin or 5-fl uorouracil (5-FU), is also active against advanced gastric cancer [10-13]. However, a relatively high incidence of grade 3 or 4 neutropenia (14%-35%) is one of the major adverse effects.Paclitaxel is known to be a cell-cycle-specifi c agent, and in vitro experiments have suggested that prolonged Results. A total of 54 patients were registered. All of them had measurable disease and were determined to be eligible for the present study. Two complete responses and 23 partial responses were confi rmed, giving an overall response rate of 46.3%. At a fi nal follow up of 3 years, the median progressionfree survival and median overall survival were 6.0 and 14.3 months, respectively. Grade 3 neutropenia occurred in 14 patients, and grade 4 in 1 patient (total, 27.8%). The most serious nonhematological toxicity was diarrhea, where grade 3 occurred in 5 patients (9.3%). There were no treatmentrelated deaths. Conclusion. A combination of weekly paclitaxel plus S-1 was found to be well tolerated and effective in patients with advanced gastric cancer. Further investigation with comparative trials is needed for confi rmation.

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