ABSTRACT
The purpose of this study was to investigate the anti-tumor effect and potential mechanisms of i.p. hyperthermia in combination with α-galactosylceramide (α-GalCer) for the treatment of ovarian cancer. In this study, immuno-competent tumor models were established using murine ovarian cancer cell lines and treated with i.p. hyperthermia combining α-GalCer. Th1/Th2 cytokine expression profiles in the serum, NK cell cytotoxicity and phagocytic activities of dendritic cells (DCs) were assayed. We also analyzed the number of CD8(+)/IFN-γ(+) tumor specific cytotoxic T cells, as well as the tumor growth based on depletion of lymphocyte sub-population. Therapeutic effect on those ovarian tumors was monitored by a non-invasive luminescent imaging system. Intra-peritoneal hyperthermia induced significant pro-inflammatory cytokines expression, and sustained the response of NK and DCs induced by α-GalCer treatment. The combination treatment enhanced the cytotoxic T lymphocyte (CTL) immune response in two mouse ovarian cancer models. This novel treatment modality by combination of hyperthermia and glycolipid provides a pronounced anti-tumor immune response and better survival. In conclusion, intra-peritoneal hyperthermia enhanced the pro-inflammatory cytokine secretion and phagocytic activity of DCs stimulated by α-GalCer. The subsequent CTL immune response induced by α-GalCer was further strengthened by combining with i.p. hyperthermia. Both innate and adaptive immunities were involved and resulted in a superior therapeutic effect in treating the ovarian cancer.
Subject(s)
Galactosylceramides/therapeutic use , Hyperthermia, Induced , Ovarian Neoplasms/drug therapy , Peritoneum/pathology , Animals , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Cell Death/drug effects , Cell Line, Tumor , Cytokines/blood , Cytokines/metabolism , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Disease Models, Animal , Female , Galactosylceramides/pharmacology , Inflammation Mediators/metabolism , Mice , Ovarian Neoplasms/pathology , Peritoneum/drug effects , Phagocytosis/drug effects , Th1 Cells/drug effects , Th1 Cells/metabolism , Th2 Cells/drug effects , Th2 Cells/metabolismABSTRACT
Response to platinum retreatment in recurrent epithelial ovarian cancer is related to the platinum-free interval (PFI). The recommended and most accepted chemotherapy in the treatment of platinum-sensitive (PFI > 6 months) recurrence is platinum-based combination regimens. Patients with a PFI of 6-12 months are often considered partially platinum-sensitive (PPS) because lower response rates to subsequent platinum retreatment have been identified. Controversies and uncertainties still exist in this population of patients regarding the best treatment and the most effective therapeutic agents. It is proposed that extending the PFI with non-platinum agents may enhance the response to and the outcome of subsequent rechallenge with platinum. In this review, we discuss the treatment for PPS recurrent ovarian cancer and the possible clinical significance of extending PFI with intent to improve the medical care of PPS recurrence.
