Show simple item record

dc.contributor.authorCooke, Marcus S.
dc.contributor.authorDuarte, Tiago L.
dc.contributor.authorCooper, Deborah
dc.contributor.authorChen, Jie
dc.contributor.authorNandagopal, Sridevi
dc.contributor.authorEvans, Mark D.
dc.date.accessioned2009-08-05T07:30:24Z
dc.date.available2009-08-05T07:30:24Z
dc.date.issued2008-12-01
dc.identifier.citationDNA Repair (Amst.) 2008, 7 (12):1982-1989en
dc.identifier.issn1568-7864
dc.identifier.pmid18793759
dc.identifier.doi10.1016/j.dnarep.2008.08.007
dc.identifier.urihttp://hdl.handle.net/10146/76333
dc.description.abstractThiopurine antimetabolites, such as azathioprine (Aza) and 6-thioguanine (6-TG), are widely used in the treatment of cancer, inflammatory conditions and organ transplantation patients. Recent work has shown that cells treated with 6-TG and UVA generate ROS, with implied oxidatively generated modification of DNA. In a study of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in renal transplant patients, we provided the first in vivo evidence linking Aza and oxidatively damaged DNA. Using the hOGG1 comet assay, we herein demonstrate high levels of 8-oxodG and alkali-labile sites (ALS) in cells treated with biologically relevant doses of 6-TG, or Aza, plus UVA. This damage was induced dose-dependently. Surprisingly, given the involvement of 6-TG incorporation into DNA in its therapeutic effect, significant amounts of 8-oxodG and ALS were induced in quiescent cells, although less than in proliferating cells. We speculate that some activity of hOGG1 towards unirradiated, 6-TG treated cells, implies possible recognition of 6-TG or derivatives thereof. This is the first report to conclusively demonstrate oxidatively damaged DNA in cells treated with thiopurines and UVA. These data indicate that Aza-derived oxidative stress will occur in the skin of patients on Aza, following even low level UVA exposure. This is a probable contributor to the increased risk of non-melanoma skin cancer in these patients. However, as oxidative stress is unlikely to be involved in the therapeutic effects of Aza, intercepting ROS production in the skin could be a viable route by which this side effect may be minimised.
dc.description.sponsorshipM.S.C. and M.D.E. are partners of ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (Contract No. 513943).en
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6X17-4TK2PHP-2&_user=1843694&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=c878b6a7a3a819e631c6f2c35a8ce9f5en
dc.subjectAzathioprineen
dc.subjectOxidative stressen
dc.subjectUV radiationen
dc.subject8-Oxo-7,8-dihydro-2′-deoxyguanosineen
dc.subjectComet assayen
dc.subject.meshAntimetabolites, Antineoplastic
dc.subject.meshAzathioprine
dc.subject.meshCell Survival
dc.subject.meshCells, Cultured
dc.subject.meshComet Assay
dc.subject.meshDNA
dc.subject.meshDNA Damage
dc.subject.meshDNA Glycosylases
dc.subject.meshDeoxyguanosine
dc.subject.meshDose-Response Relationship, Radiation
dc.subject.meshFibroblasts
dc.subject.meshHumans
dc.subject.meshOxidative Stress
dc.subject.meshReactive Oxygen Species
dc.subject.meshThioguanine
dc.subject.meshUltraviolet Rays
dc.titleCombination of azathioprine and UVA irradiation is a major source of cellular 8-oxo-7,8-dihydro-2'-deoxyguanosine.en
dc.typeArticleen
dc.identifier.journalDNA repairen
html.description.abstractThiopurine antimetabolites, such as azathioprine (Aza) and 6-thioguanine (6-TG), are widely used in the treatment of cancer, inflammatory conditions and organ transplantation patients. Recent work has shown that cells treated with 6-TG and UVA generate ROS, with implied oxidatively generated modification of DNA. In a study of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in renal transplant patients, we provided the first in vivo evidence linking Aza and oxidatively damaged DNA. Using the hOGG1 comet assay, we herein demonstrate high levels of 8-oxodG and alkali-labile sites (ALS) in cells treated with biologically relevant doses of 6-TG, or Aza, plus UVA. This damage was induced dose-dependently. Surprisingly, given the involvement of 6-TG incorporation into DNA in its therapeutic effect, significant amounts of 8-oxodG and ALS were induced in quiescent cells, although less than in proliferating cells. We speculate that some activity of hOGG1 towards unirradiated, 6-TG treated cells, implies possible recognition of 6-TG or derivatives thereof. This is the first report to conclusively demonstrate oxidatively damaged DNA in cells treated with thiopurines and UVA. These data indicate that Aza-derived oxidative stress will occur in the skin of patients on Aza, following even low level UVA exposure. This is a probable contributor to the increased risk of non-melanoma skin cancer in these patients. However, as oxidative stress is unlikely to be involved in the therapeutic effects of Aza, intercepting ROS production in the skin could be a viable route by which this side effect may be minimised.


Files in this item

Thumbnail
Name:
Publisher version

This item appears in the following Collection(s)

  • Articles
    Articles of researchers from ECNIS Network of Excellence

Show simple item record