Improving cancer therapy by investigating chemotherapeutic agents alone and in combination

Worldwide, over one million people are diagnosed each year with breast cancer. It has become apparent that monotherapies for breast cancer are likely to be limited in efficacy and thus there is the need for new therapies utilised in combination to better treat the disease. Radiotherapy is often utilised in the treatment of the disease. However, the use of radiation treatment is damaging to other non-cancerous cells within the body, especially when external beam radiation is used. One approach to enhance the efficacy and limit normal cell toxicity is to combine radiotherapy with chemosensitisers. This involves cancer cells to be radio sensitised using chemotherapeutic drugs in order to increase cell death rate to cancer cells without negatively affecting healthy tissue and leading to a reduced dose of radio therapeutic agent needing to be used in patients. AIM: The aim of this study is to discover chemotherapeutic agents and their combination treatment regimens with potential to radio sensitise breast cancer cell lines T47D, MBD-MA-231 and MCF7. METHOD: As well as investigating the naturally derived compound Resveratrol; several novel compounds known to inhibit NFkB were investigated; BMS, Su 182, Su 691, Su 759 and Su 567 alone and in combination with either PARP-inhibitor AG014361 or Cisplatin. Clonogenic Assays were used to determine the effectiveness of drugs alone and in combination with other agents on the ability of cells to successfully form colonies in vitro. FACS Analysis on the treated cells then followed in order to determine whether or not the specific treatment regime increased the likelihood of radio sensitisation by determining if there was an increase in G2/M phase of cell cycle. RESULTS: All treatments were shown to be effective at reducing cell SF in all cell lines investigated. Overall effectiveness of chemotherapeutic agents was increased when they were used in combination with either Cisplatin or PARP-inhibitor AG014361, possibly due to several internal survival mechanisms within cells being inhibited simultaneously. Combination treatment with Cisplatin had the highest proportional increase of cells experiencing G2/M phase of division, suggesting an increase in radio sensitisation following combination treatment of chemotherapeutic agents.Worldwide, over one million people are diagnosed each year with breast cancer. It has become apparent that monotherapies for breast cancer are likely to be limited in efficacy and thus there is the need for new therapies utilised in combination to better treat the disease. Radiotherapy is often utilised in the treatment of the disease. However, the use of radiation treatment is damaging to other non-cancerous cells within the body, especially when external beam radiation is used. One approach to enhance the efficacy and limit normal cell toxicity is to combine radiotherapy with chemosensitisers. This involves cancer cells to be radio sensitised using chemotherapeutic drugs in order to increase cell death rate to cancer cells without negatively affecting healthy tissue and leading to a reduced dose of radio therapeutic agent needing to be used in patients. AIM: The aim of this study is to discover chemotherapeutic agents and their combination treatment regimens with potential to radio sensitise breast cancer cell lines T47D, MBD-MA-231 and MCF7. METHOD: As well as investigating the naturally derived compound Resveratrol; several novel compounds known to inhibit NFkB were investigated; BMS, Su 182, Su 691, Su 759 and Su 567 alone and in combination with either PARP-inhibitor AG014361 or Cisplatin. Clonogenic Assays were used to determine the effectiveness of drugs alone and in combination with other agents on the ability of cells to successfully form colonies in vitro. FACS Analysis on the treated cells then followed in order to determine whether or not the specific treatment regime increased the likelihood of radio sensitisation by determining if there was an increase in G2/M phase of cell cycle. RESULTS: All treatments were shown to be effective at reducing cell SF in all cell lines investigated. Overall effectiveness of chemotherapeutic agents was increased when they were used in combination with either Cisplatin or PARP-inhibitor AG014361, possibly due to several internal survival mechanisms within cells being inhibited simultaneously. Combination treatment with Cisplatin had the highest proportional increase of cells experiencing G2/M phase of division, suggesting an increase in radio sensitisation following combination treatment of chemotherapeutic agents