This means that mismatch repair defects confer significant resistance to only a few drugs. Patients who have had successful chemotherapy often develop an unrelated leukaemia with defective mismatch repair. We plan to examine if this represents the clinical counterpart of isolating drug resistant cells in the laboratory. If it does, we hope to understand how these secondary leukaemias develop. Recombinational repair appears to influence resistance to many drugs with diverse chemical structures.
Deficient cells are very sensitive to a wide variety of chemotherapeutic agents.
This suggests that broken DNA is an important secondary product of DNA s interaction with many drugs. There appear to be important interactions between recombinational repair and the tumour suppressor protein p53. Mutations which inactivate p53 are the most common single change in human cancers and these mutations normally make the tumour cells more resistant to chemotherapy. We plan to investigate how p53 is involved in controlling drug resistance. One approach we will take is to examine whether p53 is somehow involved in controlling the outcome of recombinational repair and the fate of broken DNA ends in drug treated cells.