Exploration of 5-fluorouracil resistance mechanisms in colorectal cancer using 5-FU-resistant xenograft models

Despite therapeutic advances, colorectal cancer (CRC) still has a 45% mortality rate, and one of the major problems is the development of acquired resistance to treatment with anticancer drugs. 5-fluorouracil (5-FU) is the most commonly used drug for postoperative treatment for CRC. It acts by blocking thymidylate synthase and production of DNA in replicating cells. Whilst there is some understanding of resistance mechanisms for 5-FU, there is still clearly much that needs to be elucidated. If there was a greater understanding of the mechanisms then this could lead to the development of prognostic biomarkers which would assess the suitability of a patient to receive 5-FU as part of their treatment. In addition this understanding could lead to the development of therapeutics which could modulate the mechanisms of acquired drug resistance thus increasing the population of patients who would respond to 5-FU giving a better chance of therapeutic success.

To this end we have developed 5-FU resistant CRC cell lines and performed proteomic analyses in vitro to identify potential candidate proteins for further investigation. We have also demonstrated that these cells maintain their resistant phenotype when transplanted as subcutaneous xenograft tumours in vivo, and it is the in vivo model that will form the basis for investigation in this project.

Thus the aims of this project are to identify novel mechanisms of 5-FU resistance using the 5-FU resistant xenograft models, and to try and understand how metabolism of the drug is altered through acquired resistance. The project will also look at whether acquired resistance to 5-FU leads to resistance to other drug types.

This work should result ultimately in identification of biomarkers to monitor the success of 5-FU therapy and/or development of novel therapeutics which can help modulate resistance to 5-FU therapy and improve its chances of success.