title: Topical thymidine dinucleotide application protects against UVB-induced skin cancer in mice with DNA repair gene (Ercc1)-deficient skin.
abstract: Topical application of thymidine dinucleotides (pTpT) provides some protection against the effects of UV on the skin, however, many details of the protective mechanism have yet to be elucidated. We have used mice with an epidermis-specific knockout for the nucleotide excision repair gene, Ercc1, to investigate the mechanisms of protection. pTpT offered no protection against the pronounced UV-induced short-term erythema and skin thickening responses that are characteristic of DNA repair-deficient skin. It also had no effect on UV-induced apoptosis in Ercc1-deficient cultured keratinocytes. However, in these short-term experiments in both skin and keratinocyte culture pTpT did cause a slight reduction in proliferation. pTpT application during a chronic UV irradiation protocol provided some protection from UVB-induced skin carcinogenesis in epidermis-specific Ercc1 knockout mice. The median tumour free survival time was increased in the pTpT-treated group and treated animals had fewer tumours. In addition, pTpT-treated animals developed fewer large inwardly growing skin lesions than untreated animals. Furthermore, the proliferation response was reduced in chronically irradiated, non-lesional pTpT-treated skin. We conclude that cancer protection by pTpT in our mice is not modulated by an upregulation of DNA repair, as protection appears to be independent of a functional nucleotide excision repair pathway. We hypothesise instead that protection by pTpT is due to a reduction in epidermal proliferation.
authors.affiliation: Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Lawrence
authors.forename: Liang
authors.initials: L
authors.lastname: Song
authors.forename: Jennifer
authors.initials: J
authors.lastname: Doig
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Ritchie
authors.forename: David G
authors.initials: DG
authors.lastname: Brownstein
authors.forename: David W
authors.initials: DW
authors.lastname: Melton
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004720:Endonucleases / Q000502:physiology*; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000528:radiation effects; D004890:Erythema / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D005260:Female; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015996:Survival Rate; D013936:Thymidine / Q000008:administration & dosage*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014916:Whole-Body Irradiation
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C045073:Cre recombinase; D019426:Integrases; D004720:Endonucleases; C499360:Ercc1 protein, mouse; D013936:Thymidine