Topical Thymidine Dinucleotide Treatment Reduces Development of Ultraviolet-Induced Basal Cell Carcinoma in Ptch-1+/− Mice

Abstract

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 pTTtreated 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. 1 Like squamous cell carcinomas (SCCs), BCCs are associated with fair skin and chronic sunlight exposure, 2,3 but the relationship is more complex and studies to date have failed to show that sun protection reduces development of BCCs, in contrast to SCCs.1 Moreover, BCCs and SCCs differ in their responsiveness to certain chemopreventive agents. For example, BCC development is inhibited strongly by topical retinoids but not by oral nonsteroidal anti-inflammatory drugs (NSAIDs) or green tea.4,5 By contrast, murine SCC photocarcinogenesis is inhibited poorly by topical retinoids and quite well by oral NSAIDs or green tea. 4,6 These differing effects of UV radiation and chemopreventive agents on BCC versus SCC, in combination with the large socioeconomic burden of BCCs, 7 stimulated us to test thymidine dinucleotide (pTT), an agent already demonstrated to prevent SCCs in UV-irradiated mice 8 for its ability to reduce BCC development.Studies during the past decade have tied BCC tumorigenesis quite firmly to activated hedgehog signaling, a Research involving processing tissue for evaluation of microscopic BCCs, routine histology, immunofluorostaining image, and statistical analyses, and manuscript preparation were performed at the

Cyanidin-3-glucoside inhibits UVB-induced oxidative damage and inflammation by regulating MAP kinase and NF-κB signaling pathways in SKH-1 hairless mice skin

“…In addition, UVB unexposed skin treated with C3G presented glutathione levels similar to the unexposed controls. Moreover, UVB causes direct DNA damage by oxidation of nucleotides and produces 8-OHdG (Afaq et al , 2007; Arad et al , 2008). Employing immunofluorescence analysis, we assessed the effect of topical application of C3G on UVB-mediated DNA damage in mouse epidermis.…”

Telomere-Mediated Effects on Melanogenesis and Skin Aging

“…We were therefore intrigued to observe that the inducible component of DNA repair in mammalian cells is not error prone. Moreover, in the face of repeated mutagenic exposures to UV irradiation, cells in pTT-treated skin incurred fewer mutations than those in control skin, as determined by the quantification of either mutations in a LacZ reporter transgene (Goukassian et al, 2004) or p53-mutated keratinocyte clones in chronically irradiated skin (Arad et al, 2008). The mammalian SOS-like response in human skin thus includes at least two distinct components: enhanced melanogenesis (so-called tanning) and enhanced high-fidelity DNA repair capacity.…”

Topical delivery of DNA oligonucleotide to induce p53 generation in the skin via thymidine dinucleotide (pTT)-encapsulated liposomal carrier

“…Numerous studies also indicated that triggering p53 induction inactivates the division of cancer cells. 7,8 Thymidine dinucleotide (pTT), a fragment of an oligonucleotide, activates the p53 transcription factor and p53 protein, and triggers a cascade of DNA-repair enzymes according to in vitro and in vivo evidence which focuses on UV radiation-induced mutagenesis and carcinogenesis. 9 Typically, oligonucleotides have a high molecular weight, a negative charge, and high water solubility, which causes problems when transporting them through cellular membranes to generate specific reactions in nuclei.…”