Peter Karran

DNA Repair and Skin Cancer in Immunosuppressed Patients

Many of the drugs used in clinical practice damage DNA. The interaction between DNA repair and the DNA damage caused by therapeutic drugs is a major area of interest in the laboratory. One of the long-term hazards of drug-induced DNA damage is the cancer that develops as a consequence of treatment.

Cancer in organ transplant recipients provides one of the most dramatic examples of therapy-related malignancy. These patients receive lifelong treatment with immuno-suppressive drugs which we have shown to be associated with an increased incidence of DNA mismatch repair-defective acute myeloid leukaemia. The risk of squamous cell skin carcinoma (SCC) in organ transplant patients is more than 100-fold higher than normal - some patients develop as many as 50 separate tumours.

Two factors are implicated in this increased risk: duration of treatment with immuno-suppressive drugs, and sunlight exposure. Almost all transplant patients are treated with the immuno-suppressant azathioprine (Aza), a prodrug that causes 6-thioguanine (6-TG) to be incorporated into DNA. Unlike normal DNA bases, 6-TG absorbs UVA light and we have shown that DNA 6-TG acts as an endogenous photosensitizer for UVA. Although neither DNA 6-TG not UVA itself is particularly harmful, in combination they are mutagenic. Low doses of UVA generate reactive oxygen species (ROS) in cells with DNA 6-TG.

In addition, DNA 6-TG is converted to a photo-product(s) that block DNA replication in biochemical assays. ROS are among the most potent DNA damaging species. They produce miscoding DNA lesions and are implicated in cancer. Replication-blocking DNA damage can be bypassed in an error-prone, mutagenic, lesion tolerance strategy. These properties of combined Aza/UVA treatment suggests that mutagenic DNA damage caused by Aza and sunlight might contribute to skin cancer in immunosuppressed patients.

The relative contributions of DNA damaging ROS and 6-TG photoproducts to the effects of Aza/UVA treatment are unknown. In particular, we do not know why DNA replication is blocked. The nature of the mutagenic DNA lesions and the contribution of DNA repair in ameliorating their effects also remain largely undefined. These problems will be addressed by a combination of biochemical DNA repair assays using substrates with defined DNA damage and analysis of sensitivity of cells with defined DNA repair defects. The availability of biopsy material from patients undergoing Aza treatment also offers a complementary approach to assess the clinical impact of the photochemical sensitivity of DNA 6-TG and its possible relevance to transplant-related skin cancers.

References

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