The methylated form of DNA 6-TG miscodes during replication and it is noteworthy that azathioprine treatment is associated with a perceptible increase in mutation frequency in circulating lymphocytes [14] and with an increased risk of leukemia [12]. damage to the cellular effects of photosensitised UVA. Proteins targeted for oxidation damage include DNA repair factors and we suggest that UVA-mediated protein damage may contribute to sunlight-induced malignancy risk. interactions with cellular chromophores that act as photosensitisers to generate DNA-damaging reactive oxygen species (ROS). Depending on the distance between the chromophore and the target, UVA irradiation can also result in one-electron abstraction and the formation of a reactive radical cation. Importantly, UVA-generated ROS damage other biomolecules including proteins and lipids, and this non-DNA photodamage may be an important contributor to the biological effects of UVA such as carcinogenesis and photoaging. Endogenous UVA chromophores have not been fully characterized, although porphyrins, flavins [3], melanin [4] and UVB photoproducts of tryptophan (6-formylindolo[3,2-purine synthesis resulting in an inadequate supply Olutasidenib (FT-2102) of purine nucleotides for replication and transcription [7] and interference with intracellular signalling pathways competition for GTP binding by G proteins [8], [9]. Thioguanine nucleotides are substrates for incorporation into DNA and to a lesser degree into RNA and the biological effects of thiopurines are at least partly dependent on the formation of DNA 6-TG [7], [10]. DNA 6-TG may undergo non-enzymatic Olutasidenib (FT-2102) methylation that can provoke ultimately lethal processing by DNA mismatch PRKM1 repair [11], [12]. Alternatively, it can participate in the formation of DNA interstrand-crosslinks [13] that are highly toxic in a mismatch repair-independent manner. The methylated form of DNA 6-TG miscodes during replication and it is noteworthy that azathioprine treatment is usually associated with a perceptible increase in mutation frequency Olutasidenib (FT-2102) in circulating lymphocytes [14] and with an increased risk of leukemia [12]. Most striking, however, is the greater than 100-fold higher risk of skin malignancy in immunosuppressed organ transplant patients [15], most of whom will have been prescribed azathioprine and whose skin contains detectable amounts of DNA 6-TG [16]. Its more intermittent use in the management of inflammatory bowel disease entails a lower, but still significant skin malignancy risk [17], [18], [19]. Sunlight exposure is a contributory factor in thiopurine-related skin cancer. The skin of patients taking azathioprine is usually photosensitive to UVA but not to UVB, consistent with the absorbance maximum of DNA 6-TG at around 340?nm. This has led to the suggestion that this photochemical reactions of azathioprine or its metabolites [20] may contribute to skin malignancy risk [21]. Open in a separate windows Fig. 1 Structures of UVA photosensitisers. Azathioprine, mercaptopurine and 6-thioguanine are all converted to 6-TG deoxyribonucleotides, which are in turn incorporated into DNA. This is a prerequisite for the clinical effectiveness of thiopurines. Thiopyrimidine deoxynucleosides are incorporated Olutasidenib (FT-2102) into DNA of cells the TK-dependent pyrimidine nucleoside salvage pathway. The fluoroquinolone class of antibiotics acts as inhibitors of DNA topoisomerases and intercalate rather than incorporate into DNA. ii) the TK-dependent pyrimidine nucleoside salvage pathway [24]. Despite its accumulation to higher levels than DNA 6-TG and the ability to undergo facile methylation, DNA S4T is not detectably harmful. The absence of cytotoxicity has been ascribed to the preferential formation of structurally and thermodynamically good base pairs by both DNA S4T and its methylated counterpart that obviates their engagement by DNA mismatch repair, the major contributor to DNA 6-TG toxicity [25]. DNA S4T is usually, however, extremely cytotoxic in combination with low doses of UVA [24]. Recently, 2,4-dithiothymidine has been shown to be comparable or superior to 4-thiothymidine as a photosensitiser.