Previous and current research
Because many antitumour drugs damage DNA, their effectiveness is significantly affected by DNA repair. We are investigating the relationship between DNA repair and drug resistance and trying to apply this knowledge to cancer development. Our principal focus is on DNA mismatch repair - an important replication editing mechanism. Mismatch repair is defective in many human cancers. The repair-defective cancers are highly resistant to methylating agents and thiopurine bases ¿ both important therapeutic drugs. In the laboratory we can isolate mismatch repair deficient cells simply by selecting for resistance to methylating agents or the thiopurine 6-thioguanine.

In the past, these cells have provided useful information about how mismatch repair can interact with DNA damage and allowed us to identify the DNA lesions with which mismatch repair interacts. Patients who have had successful chemotherapy sometimes develop a mismatch repair defective secondary leukaemia. We have demonstrated that similar repair defects are associated with leukaemia in organ transplant patients immunosuppressed with the thiopurine prodrug azathioprine. These findings suggest that repair defective AML may sometimes be the clinical counterpart of selection for drug resistant laboratory cells.

Future projects
We will continue to investigate mismatch repair deficiency in secondary leukaemias. It is now clear that cells with reduced mismatch repair capacity are more mutable by many different kinds of DNA damage. This has important implications for therapy involving DNA damaging drugs. We are therefore examining whether the extraordinary susceptibility to skin cancer in azathioprine immunosuppressed organ transplant patients is associated with reduced mismatch repair levels.

Thiobases have distinctive photochemical properties. As part of this study, we are examining the photochemical properties of thiopurines - particularly their susceptibility to oxidative damage by UVA radiation. This is a potentially mutagenic treatment and sunlight is an important cofactor in transplant related skin cancer. This study is part of a general interest in the interactions between oxidative DNA damage and mismatch repair. We are also examining the photochemical properties of some novel thiopyrimidine deoxynucleosides to determine whether their UVA susceptibility might have therapeutic potential.