Cytotoxicity of platinum compounds & gamma-radiation in human ovarian & testicular cancers.

摘要

Cancer is a disease that continues to be a challenging problem all over the world. It is a disease that may be cured, but can also be recurrent. Patients constantly struggle with the battle over cancer, but frequently lose. Resistance to conventional treatments is one cause as to why patients succumb to the disease. Two conventional treatments are the use of cisplatin for chemotherapy and gamma-radiation for radiotherapy. These treatments are initially effective, but due to resistance, the cancer may stop responding and continue to grow and spread. Efforts are being made to invent novel treatments or to use combinations of conventional treatment to overcome resistance. Ovarian and testicular cancers are just two of many types of cancers that have the potential to be treated or cured with new treatments. In order to design new treatments to overcome resistance, DNA damage induction, DNA repair, gene expression, and cell death from cytotoxic agents need to be understood. In this study, the cytotoxicity and amount of DNA double strand breaks (DSBs) of two different platinum compounds, cisplatin and dach-2, in two ovarian cancer cell lines, A2780 and C30, and on testicular cell line, Tera-2, were investigated. Also, DNA damage by analysis of foci formation, H2AX expression, and degree of apoptosis due to cisplatin, gamma-radiation, and a combination of cisplatin and gamma-radiation were examined. Results indicated dach-2 was less toxic than cisplatin and had the ability to overcome cross resistance to cisplatin and carboplatin. In addition, dach-2 was found to have a lack of DNA-damaging capability and actually enhances repair of normal levels of DNA DSBs. For Tera-2 cells, addition of cisplatin to gamma-radiation did not produce a synergistic effect or even an additive effect. The combination did not induce more DNA damage or have a higher H2AX expression than either cytotoxic agent alone. This indicates the combination did not increase the number of DNA DSBs, and thus did not lead to an increase expression in H2AX greater than either treatment alone. The DNA damage response (DDR) is important for repairing DNA DSBs. A lower H2AX expression is correlated with a decrease in the DDR. Therefore, addition of cisplatin to gamma-radiation for treatment of testicular cancer will not be more effective.