Topical thymidine dinucleotide treatment reduces development of ultraviolet-induced basal cell carcinoma in Ptch-1+/- mice.
Treatment with thymidine dinucleotide (pTT) has well documented DNA-protective effects and reduces development of squamous cell carcinoma in UV-irradiated mice. The preventive effect of pTT on basal cell carcinoma (BCC) was evaluated in UV-irradiated Ptch-1(+/-) mice, a model of the human disease Gorlin syndrome. Topical pTT treatment significantly reduced the number and size (P < 0.001) of BCCs in murine skin after 7 months of chronic irradiation. Skin biopsies collected 24 hours after the final UV exposure showed that pTT reduced the number of nuclei positive for cyclobutane pyrimidine dimers by 40% (P < 0.0002) and for 8-hydroxy-2'-deoxyguanosine by 61% (P < 0.01 compared with vehicle control). Immunostaining with an antibody specific for mutated p53 revealed 63% fewer positive patches in BCCs of pTT-treated mice compared with controls (P < 0.01), and the number of Ki-67-positive cells was decreased by 56% (P < 0.01) in pTT-treated tumor-free epidermis and by 76% (P < 0.001) in BCC tumor nests (P < 0.001). Terminal dUTP nick-end labeling staining revealed a 213% increase (P < 0.04) in the number of apoptotic cells in BCCs of pTT-treated mice. Cox-2 immunostaining was decreased by 80% in tumor-free epidermis of pTT-treated mice compared with controls (P < 0.01). We conclude that topical pTT treatment during a prolonged period of intermittent UV exposure decreases the number and size of UV-induced BCCs through several anti-cancer mechanisms.
Arad
Simin
S
Department of Dermatology, Boston University School of Medicine, 609 Albany St., Boston, MA 02118, USA.
Zattra
Edoardo
E
Hebert
Jennifer
J
Epstein
Ervin H
EH
Goukassian
David A
DA
Gilchrest
Barbara A
BA
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000279:Administration, Cutaneous; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis; D001478:Basal Cell Nevus Syndrome; D002280:Basal Cell Carcinoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002467:Cell Nucleus / Q000187:drug effects; D048429:Cell Size; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D051379:Mice; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011740:Pyrimidine Dimers / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000517:prevention & control*; D013942:Thymine Nucleotides / Q000008:administration & dosage / Q000627:therapeutic use*; D014466:Ultraviolet Rays
D016588:Anticarcinogenic Agents; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011740:Pyrimidine Dimers; D011956:Receptors, Cell Surface; D013942:Thymine Nucleotides; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine