ABSTRACT
Gene therapy, using cytokine gene transduction, aims to increase the antigenicity of tumor cells, and to activate the immune effector cells, and thereby inducing tumor regression. With regards to in vitro sensitivity to peripheral blood monocytes and in vivo tumorigenic activity we compared the differences between parent hepatoma cell lines and interleukin-2 (IL-2) transduced hepatoma cell lines using N2A/IL-2 and LNC/IL-2 retrovirus. IL-2 secretion was 186 pg/10(6) cells/24 h in SK-Hep1 cell line and 147 pg/106 cells/24 h in Hep-3B cell line with N2A/IL-2 retroviral vector and was 55,000 pg/10(6) cells/24 h in Hep-3B cell line with LNC/IL-2 retroviral vector. in vitro sensitivity to peripheral blood monocytes was increased by 163.8-254% in IL-2 transduced hepatoma cell lines (Hep-3B/LNC/IL-2, Hep-G2/LNC/IL-2) compared to those of the parent cell lines. The tumor was formed in 1 of 3 BALB/c mice and all 3 nude mice with the injection of 1x107 cells. Simultaneous injection of 1x10(7) cells of the parent cell line (Hep-3B) into the right flank and IL-2 transduced cell line (Hep-3B/LNC/IL-2) into the left flank of the three BALB/c mice and of 5x10(5) cells for the three nude mice resulted in a complete regression of the IL-2 modified tumor cell line (Hep-3B/LNC/IL-2) in 3 weeks and the parent cell line (Hep-3B) in 5 weeks. After injection of 1x10(7) cells into five other nude mice, the tumor of the IL-2 transduced hepatoma cells (Hep-3B/LNC/IL-2) gradually disappeared, however, the tumor of the parent hepatoma cell line initially decreased and then gradually regrew 20 days later. In conclusion, IL-2 transduced hepatoma cell lines secreting IL-2 became more sensitive to peripheral blood monocytes. IL-2 secretion by LNC/IL-2 retrovirus from the hepatoma cell lines was more prominent compared with that by N2A/IL-2 retrovirus. IL-2 transduction into the hepatoma cells resulted in increased antigenicity to the tumors formed by IL-2 transduced hepatoma cell line and parent cell line, which leads the regression of the tumors. However, the higher the tumor burden, the less efficient tumor regression by IL-2 transduction into the hepatoma cell line in nude mice was observed.
Subject(s)
Carcinoma, Hepatocellular/pathology , Genetic Therapy , Genetic Vectors/genetics , Interleukin-2/physiology , Retroviridae/genetics , Animals , Cytotoxicity, Immunologic , Humans , Interleukin-2/genetics , Interleukin-2/metabolism , Leukocytes, Mononuclear/immunology , Liver Neoplasms, Experimental/pathology , Liver Neoplasms, Experimental/therapy , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Recombinant Fusion Proteins/metabolism , Recombinant Fusion Proteins/physiology , Tumor Cells, Cultured/metabolism , Tumor Cells, Cultured/transplantationABSTRACT
The relationship between p53 overexpression and clinicopathologic variables in gastric cancer was evaluated using 304 paraffin-embedded gastric tumor tissues. DO7, a murine monoclonal antiserum to p53 protein, was used for the immunohistochemical analysis. Positive staining was found in 129 tumors (42.2% of all tumors). Overexpression of p53 was not associated with sex, location of the tumor in the stomach or the type of Borrman's tumor. The overexpression rate of p53 protein was 30.4% (28/92) in stage II and 47.6% (101/212) in stage III (p = 0.007). While there was no significant association between p53 protein accumulation and T stage, there was a significant association with N stage, i.e. p53 overexpression was 27.4% (17/62) in the node-negative group and 46.3% (112/242) in the node-positive group (p = 0.011). In 79 patients, in whom corresponding primary gastric tumor and regional lymph node metastases were available, overexpression was found in 34 (43%) primary tumors and in 38 (48.1%) node samples, with a concordance rate of 67.1% in terms of p53 expression. Mean numbers of regional lymph node involvement by the tumor were 6.1 in the group with p53 overexpression and 5.2 in the group showing no immunoreactivity (p = 0.051). These findings suggest that p53 overexpression is related to gastric cancer progression and that immunoreactivity in the metastatic lymph nodes show the dependency on p53 expression in the primary tumor.
Subject(s)
Adenocarcinoma/metabolism , Gene Expression Regulation, Neoplastic , Stomach Neoplasms/metabolism , Tumor Suppressor Protein p53/biosynthesis , Adenocarcinoma/pathology , Disease Progression , Female , Humans , Male , Stomach Neoplasms/pathology , Up-RegulationABSTRACT
An immunohistochemical stain to the c-ErbB-2 protein was performed in 225 paraffin-embedded tissue blocks from patients with locally advanced gastric cancer who underwent curative resection. The overexpression of the c-ErbB-2 protein was observed in 27.4% of the patients. The c-ErbB-2 positivity showed a statistically significant correlation with nodal status and stage. The patients with an overexpression of the c-ErbB-2 protein had a tendency to a shorter survival than those without, but it was not statistically significant (p = 0.08). The 5-year survival rate after surgery was 54% in the negative staining group to the c-ErbB-2 protein and 49% in the positive staining group. This suggests that the c-ErbB-2 protein has a possible role in lymph node metastasis. Therefore overexpression of the c-ErbB-2 protein is a useful indicator of disease progression in gastric carcinoma patients who received curative surgery.