Topical thymidine dinucleotide application protects against UVB-induced skin cancer in mice with DNA repair gene ( Ercc1)-deficient skin

• Published in: DNA repair 2009-05, Vol.8 (5), p.664-671
• Main Authors: Lawrence, Nicola J., Song, Liang, Doig, Jennifer, Ritchie, Ann-Marie, Brownstein, David G., Melton, David W.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - radiation effects; Bacteriology; Biological and medical sciences; Blotting, Western; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Cells, Cultured; Dermatology; DNA Damage; DNA repair; DNA Repair - genetics; DNA-Binding Proteins - physiology; Endonucleases - physiology; Epidermis - cytology; Epidermis - drug effects; Epidermis - radiation effects; Erythema - metabolism; Erythema - pathology; Erythema - prevention & control; Female; Fundamental and applied biological sciences. Psychology; Growth, nutrition, cell differenciation; Immunoenzyme Techniques; Integrases - metabolism; Keratinocytes - cytology; Keratinocytes - drug effects; Keratinocytes - radiation effects; Male; Medical sciences; Mice; Mice, Knockout; Microbiology; Molecular and cellular biology; Molecular genetics; Mutagenesis. Repair; Neoplasms, Radiation-Induced - metabolism; Neoplasms, Radiation-Induced - pathology; Neoplasms, Radiation-Induced - prevention & control; Nucleotide excision repair; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Skin Neoplasms - prevention & control; Survival Rate; Thymidine - administration & dosage; Tumors of the skin and soft tissue. Premalignant lesions; Ultraviolet irradiation; Ultraviolet Rays - adverse effects; Whole-Body Irradiation
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2009.01.020

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.