Enhancement of DNA repair using topical T4 endonuclease V does not inhibit melanoma formation in Cdk4(R24C/R24C)/Tyr-Nras(Q61K) mice following neonatal UVR.
To further investigate the use of DNA repair-enhancing agents for skin cancer prevention, we treated Cdk4(R24C/R24C)/Nras(Q61K) mice topically with the T4 endonuclease V DNA repair enzyme (known as Dimericine) immediately prior to neonatal ultraviolet radiation (UVR) exposure, which has a powerful effect in exacerbating melanoma development in the mouse model. Dimericine has been shown to reduce the incidence of basal-cell and squamous cell carcinoma. Unexpectedly, we saw no difference in penetrance or age of onset of melanoma after neonatal UVR between Dimericine-treated and control animals, although the drug reduced DNA damage and cellular proliferation in the skin. Interestingly, epidermal melanocytes removed cyclobutane pyrimidine dimers (CPDs) more efficiently than surrounding keratinocytes. Our study indicates that neonatal UVR-initiated melanomas may be driven by mechanisms other than solely that of a large CPD load and/or their inefficient repair. This is further suggestive of different mechanisms by which UVR may enhance the transformation of keratinocytes and melanocytes.
Genetics & Population Health Division, Queensland Institute of Medical Research, Brisbane, Qld, Australia. elke.hacker@qimr.edu.au
Elke
E
Hacker
H Konrad
HK
Muller
Nicholas
N
Hayward
Paul
P
Fahey
Graeme
G
Walker
D000287:Administration, Topical; D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D043224:Deoxyribonuclease (Pyrimidine Dimer) / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011740:Pyrimidine Dimers / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D013995:Time; D016896:Treatment Outcome; D014466:Ultraviolet Rays / Q000009:adverse effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014764:Viral Proteins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D011740:Pyrimidine Dimers; D014764:Viral Proteins; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; C470698:endonuclease V, phage T4; D043224:Deoxyribonuclease (Pyrimidine Dimer)