In an effort to develop a novel treatment for gynecologic malignancies, anti-sense constructs are being used to target a critical growth factor receptor gene (the insulin-like growth factor-1 (IGF-1) receptor gene). Other investigators have demonstrated that disruption of IGF-1 receptor gene expression in certain tumor cells can lead to enhanced immune rejections of established metastatic implants in vivo. Initially, we demonstrated the presence of IGF-1 receptor in eight of eight human cervical cancer cell lines and characterized functional (growth) and physical (dissociation constants, receptor expression) aspects of these eight cell lines. In addition, we have shown that platelet-derived growth factor (PDGF) enhances IGF1 receptor gene expression and confers a growth advantage to cervical cancer cells co-incubated with both IGF-1 and PDGF. Because IGF-1 is a critical progression factor in many cell types and appears to have potent mitogenic activity in cervical cancer cells, it's receptor is a rational target for antisense therapy. Human cervical cells are being transfected with plasmids containing an antisense construct to the IGF-1 receptor gene. It is expected that these transfected cells will be significantly growth impaired. In order to develop an animal model to test the therapeutic potential of this approach to enhance immune rejection of established tumor implants in vivo, MCA-induced mouse sarcoma cells (which are generally quite non-immunogenic) are also being transfected. Once stable transfectants have been established and characterized in vitro, they will be inoculated into mice already bearing metastatic tumors and responses observed. We plan to excise the metastatic lesions following inoculation of the transfected cells to determine if a cellular immune responses has been mounted. If our results compare favorably with the results of other investigators, we expect to test this type of therapy in a clinical trial.
