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4266 Background: The aim of this dosing-finding study was to determine the maximum- tolerated dose (MTD), the dose-limiting toxicities (DLTs) and to define the recommended dose of biweekly oxalipla...

Current breast cancer (BC) treatments such as chemotherapy and radiotherapy has low specificity for cancer cells, thus also damage normal tissues. Cancer-targeting gene therapy has showed great promise to minimize treatment side effects and the risk of developing resistance. To develop a specific promoter for BC-targeting gene therapy, we identified six candidate BC-specific genes from published gene expression profile data. The promoter of one of them was shown to possess BC-specific activity in vitro, and named as BCSP. Deletion mutant analysis showed that the minimal promoter of BCSP retained BC-specific activity. In order to increase promoter activity for clinical use in gene therapy, an enhancer sequence from a promoter known to have strong activity was connected to the minimal BCSP, and the construct was named enhanced BC-specific promoter, EBP. To determine the activity of EBP, we performed reporter assays in cell lines and an orthotopic BC xenograft mouse model. In mouse model, EBP activity was higher than that of CMV promoter in tumor, and less than 10% of CMV promoter activity in normal organs such as lung and heart. Similar results were seen in cell lines. These results suggested that EBP is a strong BC-specific promoter for gene therapy. To test its therapeutic efficacy, EBP was used to drive the expression of BikDD (Bik mutant with more potent pro-apoptotic activity). We found that this therapeutic construct, EBP-BikDD, selectively killed BC cells rather than normal breast epithelial cells, in in vitro viability assay. The therapeutic effect of the liposome-complexed EBP-BikDD was then evaluated in orthotopic BC xenograft mouse model through intravenously injection. EBP-BikDD suppressed tumor growth and extended the life span of tumor-bearing mice significantly. Moreover, in situ hybridization showed that both EBP and the CMV promoter drove mRNA expression of BikDD in breast tumors, but EBP induced much lower BikDD expression in normal organs (e.g. heart) than CMV did. In conclusion, we have developed a strong and highly specific promoter for BC-targeting gene therapy. This therapy effectively suppresses human breast tumor growth in animal model and is much less toxic for normal tissues than the CMV promoter, which is widely used in current cancer gene therapy.

The current study assessed the efficacy and safety of biweekly oxaliplatin combining oral tegafur-uracil/leucovorin in treating chemonaive patients with advanced gastric cancer.Eligible patients were 18-75 years old, had stage IV disease or post-surgery recurrence, no prior palliative chemotherapy, and an ECOG performance status of 0-2. Patients in the current study received 2-h i.v. infusion of oxaliplatin at a dose of 100 mg/m(2) after diluting in 500 mL 5% dextrose/water (dexan premedication), and 5-HT3 antagonist biweekly. Oral tegafur-uracil and leucovorin was given at a dose of 300 mg/m(2)/day and 60 mg/day three times daily from day 1 to 21, respectively, followed by a 1-week rest. Response assessment was based on the RECIST criteria and was performed every two courses. Toxicity was assessed according to NCI common toxicity criteria version 2.From October 2003 to April 2006, 57 patients were evaluated (55 eligible) with a median age of 61 years (range 31-75). According to the assessment of response in 48 evaluable patients, partial response rate was 24/48 (50.0%) (95% CI: 35.23-64.73%) and stable disease was observed in 11 patients (22.92%), and diseased progressed in 13 patients (27.08%). Mean number of oxaliplatin cycles was 3 (0.5-6.5). Median time to progression was 177 days. Median overall survival was 318 days. Major-grade (III/IV) toxicities were diarrhea 25.5%, vomiting 16.5%, anemia 10.9%, numbness 12.7%, thrombocytopenia 7.3%, neutropenia 3.6% and leucopenia 1.8%.Biweekly, oxaliplatin combining oral tegafur-uracil/leucovorin in treating patients with advanced gastric cancer showed acceptable activity and manageable toxicity.

4003Background: Patients (pts) with advanced HCC and elevated AFP have a poorer prognosis compared to the general HCC population, and need effective, well tolerated treatment options. Increased VEG...