The London Research Institute research groups are based at Lincoln’s Inn Fields and Clare Hall. Our major research themes are: the biology of tumours and tissues, cellular regulatory mechanisms and genomic integrity and cell cycle.
Peter Karran : Mammalian DNA Repair
Goals
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 treatment and trying to apply this knowledge to cancer development. Our previous work on DNA mismatch repair - an important replication editing mechanism - demonstrated an important influence on the toxicity of thiopurines - an important class of anticancer and immunosuppressive drugs. We demonstrated that leukaemia in organ transplant patients immunosuppressed with the thiopurine prodrug azathioprine, is frequently mismatch repair deficient - replicating what we observe in laboratory studies of acquired thiopurine resistance. More recent work has highlighted an interaction between thiopurines and sunlight that may contribute to the extremely high risk of skin cancer in patients taking these drugs.
Future projects
We are examining whether the extraordinary susceptibility to skin cancer in azathioprine immunosuppressed organ transplant patients reflects an interaction between DNA 6-thioguanine (6-TG) - the result of azathioprine treatment - and UVA radiation in sunlight. Sunlight is an important cofactor in transplant related skin cancer. DNA 6-TG has distinctive photochemical properties - particularly its susceptibility to oxidative damage by UVA. We are investigating what kinds of UVA-induced DNA lesions are associated with thiopurine treatment. This study is part of a general interest in the interactions between UVA and DNA thiobases. We are also examining the photochemical properties of some novel thiopyrimidine deoxynucleosides to determine whether their UVA susceptibility might have therapeutic potential.
Selected Papers
Gueranger Q, Kia A, Frith D, Karran P. Crosslinking of DNA repair and replication proteins to DNA in cells treated with 6-thioguanine and UVA. Nucleic Acids Res. 2011;39(12):5057-66
(Abstract)
Pridgeon SW, Heer R, Taylor GA, Newell DR, O'Toole K, Robinson M, Xu YZ, Karran P, Boddy AV.Thiothymidine combined with UVA as a potential novel therapy for bladder cancer. Br J Cancer. 2011;104(12):1869-76
(Abstract)
Brem R, Li F, Montaner B, Reelfs O, Karran P. DNA breakage and cell cycle checkpoint abrogation induced by a therapeutic thiopurine and UVA radiation. Oncogene. 2010;29(27):3953-63
(Abstract)
Perrett CM, Harwood CA, McGregor JM, Warwick J, Cerio R, Karran P. Expression of DNA mismatch repair proteins and MSH2 polymorphisms in nonmelanoma skin cancers of organ transplant recipients. Br J Dermatol. 2010;162(4):732-42
(Abstract)
Ren X, Li F, Jeffs G, Zhang X, Xu YZ, Karran P. Guanine sulphinate is a major stable product of photochemical oxidation of DNA 6-thioguanine by UVA irradiation. Nucleic Acids Res. 2010;38(6):1832-40
(Abstract)
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Peter Karran
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