Topical DNA oligonucleotide therapy reduces UV-induced mutations and photocarcinogenesis in hairless mice.
UV-induced DNA damage gives rise to mutations and skin cancer. We have previously reported that treatment of skin cells in vitro with thymidine dinucleotide (pTT) activates p53 and increases the ability of cells to repair subsequent UV-induced DNA damage by enhancing endogenous DNA repair capacity. Here we show that topical pTT pretreatment enhances the rate of DNA photoproduct removal, decreases UV-induced mutations, and reduces photocarcinogenesis in UV-irradiated hairless WT repair-proficient and Xpc(+/-) heterozygous partially repair-deficient mice, both transgenic for the lacZ/pUR288 mutation-indicator gene. These data support the existence of inducible mammalian DNA damage responses that increase DNA repair capacity after DNA damage and hence reduce the impact of future exposures to environmental carcinogens. The ability of topically applied pTT to induce protective physiologic responses that normally result from DNA damage suggests a previously undescribed means of reducing skin cancer in high-risk individuals.
Goukassian
David A
DA
Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA. dgoukass@bu.edu
Helms
Elizabeth
E
van Steeg
Harry
H
van Oostrom
Conny
C
Bhawan
Jag
J
Gilchrest
Barbara A
BA
D000287:Administration, Topical; D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects; D051379:Mice; D008812:Mice, Hairless; D009154:Mutation / Q000187:drug effects* / Q000528:radiation effects; D009369:Neoplasms / Q000517:prevention & control*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology*; D011740:Pyrimidine Dimers; D012878:Skin Neoplasms / Q000517:prevention & control; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects; D014466:Ultraviolet Rays; D015854:Up-Regulation
D016587:Antimutagenic Agents; D009838:Oligodeoxyribonucleotides; D011740:Pyrimidine Dimers; D016159:Tumor Suppressor Protein p53