ABSTRACT
BACKGROUND: We have previously reported that irradiation of mice in utero significantly increased the tumor incidence in the offspring of irradiated mothers. The joint effects of irradiation and cigarette smoking (CS) on tumor incidence and on the process of carcinogenesis were investigated. MATERIALS AND METHODS: Pregnant C57Bl/6J female mice were irradiated with a single dose of gamma-ray (1 Gy or 3 Gy) and/or exposed to CS of IR3 non-filtered cigarettes before or during pregnancy, tumors were investigated both with histological and immunohistochemical methods. RESULTS: Longer exposure (60 days) of the mice to CS before pregnancy and irradiation during pregnancy significantly increased the tumor incidence in the mothers and their offspring. Parallel activation of Caspase-8 and inactivation of Caspase-9 was found. CONCLUSION: Joint exposure of mice to prolonged CS before pregnancy and irradiation during pregnancy significantly increased the tumor incidence both in the mothers and their offspring.
Subject(s)
Gamma Rays/adverse effects , Maternal Exposure , Smoking/adverse effects , Animals , Caspase 8/metabolism , Caspase 9/metabolism , Enzyme Activation , Female , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Neoplasms/etiology , Neoplasms/prevention & control , Pregnancy , Pregnancy, AnimalABSTRACT
Mouse glioma 261 (Gl261) cells are used frequently in experimental glioblastoma therapy; however, no detailed description of the Gl261 tumor model is available. Here we present that Gl261 cells carry point mutations in the K-ras and p53 genes. Basal major histocompatibility complex (MHC)I, but not MHCII, expression was detected in Gl261 cells. The introduction of interferon-gamma-encoding genes increased expression of both MHCI and MHCII. A low amount of B7-1 and B7-2 RNA was detected in wild-type cells, but cytokine production did not change expression levels. Gl261 cells were transduced efficiently by adenoviral vectors; the infectivity of retroviral vectors was limited. Low numbers of transplanted Gl261 cells formed both subcutaneous and intracranial tumors in C57BL/6 mice. The cells were moderately immunogenic: prevaccination of mice with irradiated tumor cells 7 days before intracranial tumor challenge prevented tumor formation in approximately 90% of mice. When vaccination was carried out on the day or 3 days after tumor challenge, no surviving animals could be found. In vitro-growing cells were radiosensitive: less than 2 Gy was required to achieve 50% cell mortality. Local tumor irradiation with 4 Gy X-rays in brain tumor-bearing mice slowed down tumor progression, but none of the mice were cured off the tumor. In conclusion, the Gl261 brain tumor model might be efficiently used to study the antitumor effects of various therapeutic modalities, but the moderate immunogenicity of the cells should be considered.
Subject(s)
Brain Neoplasms/genetics , Brain Neoplasms/immunology , Cell Line, Tumor/physiology , Disease Models, Animal , Glioblastoma/genetics , Glioblastoma/immunology , Adenoviridae/genetics , Animals , Cell Line, Tumor/radiation effects , Genetic Vectors , Histocompatibility Antigens/genetics , Histocompatibility Antigens/metabolism , Mice , Mutation , NIH 3T3 Cells , Proto-Oncogene Proteins c-myc/metabolism , Radiation Tolerance , Retroviridae/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transduction, Genetic , Tumor Suppressor Protein p53/metabolismABSTRACT
The combined therapeutic effect of cytokine-producing cancer cell vaccines and local radiotherapy was studied in a mouse glioma 261 (GI261) brain tumor model. Brain tumor-bearing mice were treated with cytokine (IL -4, IL-6, IL-7, GM-CSF, TNF-alpha, LIF, LT) producing vaccines made by in vitro transduction of GI261 cells with the corresponding adenoviral vectors. Vaccines producing either IL-4 or GM-CSF cured 20-40% of mice. The antitumor effect strongly depended on the secreted cytokine level. Vaccination therapy induced specific activation of cytotoxic T lymphocytes measured by cell-mediated cytotoxicity assay. Brain tumors were heavily infiltrated by CD4+ lymphocytes after treatment with IL-4- or GM-CSF-secreting cells. GM-CSF vaccination induced moderate CD8+ infiltration, as well. Depleting either CD4+ or CD8+ lymphocyte subsets abolished the anticancer effect of GM-CSF-expressing cells. Strong synergism was observed by combining cytokine vaccination (GM-CSF, IL-4, IL-12) with local tumor irradiation: about 80-100% of the glioma-bearing mice was cured. The high efficiency of combined treatment was maintained even under suboptimal conditions when neither of the modalities cured any of the mice alone. This suggests that vaccination therapy might open a new potential in the clinical treatment of high-grade gliomas when applied as adjuvant to existing treatment modalities.
