Skin cancer prevention: a review of current topical options complementary to sunscreens.

The incidence of non-melanoma skin cancer (NMSC) is dramatically increasing worldwide, despite the increased use of improved sunscreens. In 2014, the Surgeon General estimated that 2.2-5.0 million people were treated annually for NMSC. As the number of newly diagnosed skin cancers continues to rise, there is a need for additional preventative measures beyond sunscreens. Several newer topical products that focus on boosting DNA repair, modulating DNA transcription, decreasing inflammation and selectively targeting precancerous cells may play an important role in future skin cancer prevention.

DNA Repair Enzyme Containing Lip Balm for the Treatment of Actinic Cheilitis: A Pilot Study

Background: DNA repair enzymes have been shown to reduce actinic keratoses and non-melanoma skin cancers, but their use for the treatment of actinic cheilitis has not been studied. Objective: The purpose of this pilot study was to examine the efficacy of a DNA repair enzyme lip balm containing T4 endonuclease in reducing the severity of actinic cheilitis in patients who applied the lip balm twice daily for 3 months. Methods: We performed a prospective study in which 29 patients with a diagnosis of actinic cheilitis underwent a 3-month trial using a topical DNA repair enzyme lip balm containing T4 endonuclease applied to the lips twice daily. The primary, objective outcome was percent of actinic lip involvement, measured using computer software by dividing the calculated affected surface area by the calculated total surface area. Additional outcomes included pre- and post-intervention determination of an actinic cheilitis score on the Actinic Cheilitis Scale, which visually and tactilely quantifies the percentage of lip involvement, amount of roughness, erythema, and tenderness as well as a physician assessment using the Global Aesthetic Improvement Scale. Results: Twenty-five of the 29 enrolled patients completed the trial. The lip balm significantly decreased the percentage of affected lip surface area (P<0.0001). According to the Actinic Cheilitis Scale, data demonstrate that the lip balm significantly decreased the percentage of lip involvement (P=0.002), amount of roughness (P=0.0012)), erythema (P=0.0020), and tenderness (P=0.0175). The total Actinic Cheilitis Scale score also significantly improved after the 3-month treatment period (P<0.0001). According to the Global Aesthetic Improvement Scale, the average score for all 26 patients was 1.04. Conclusion: This study suggests that topical DNA repair enzyme lip balm containing T4 Endonuclease could potentially be a safe and efficacious way to improve and treat actinic cheilitis. J Drugs Dermatol. 2019;18(6):576-579

Improvement of Actinic Keratoses Using Topical DNA Repair Enzymes: A Randomized Placebo-Controlled Trial.

BACKGROUND: Actinic keratoses (AKs) are proliferations of abnormal keratinocytes, which may progress into non-melanoma skin cancers. Although multiple treatment modalities exist for AKs, their incidence continues to rise, making new methods of both prevention and treatment necessary. DNA repair enzymes have been shown to reverse sun-damage, resulting in reduced rates of AKs and non-melanoma skin cancer (NMSC) in specific patient populations. OBJECTIVE: We investigated the efficacy of a topical DNA repair enzyme lotion as a field therapy for AKs. METHODS: In a single center, randomized double-blind study, we randomly assigned 15 patients with AKs on their face or scalp to receive topical DNA repair enzyme lotion or placebo (Eucerin Professional lotion). Lotion was self-applied to a treatment field twice daily for 8 consecutive weeks. Complete clearance (primary outcome) was assessed at week 8, and local reactions were quantitatively measured. Follow-up at week 12 assessed for continued clearance of AKs. RESULTS: Thirteen subjects completed the trial. Compared to baseline, patients who used the repair enzyme had significantly fewer AKs than those using the control lotion after 8-weeks treatment. Specifically, there was a 46.6% percent decrease in AKs the DNA repair enzyme lotion group compared to a 32.7% decrease in the placebo group. Significance between the two groups was noted at the12 week follow-up, where there was an additional 29.2% decrease in AK percentage in the DNA repair enzyme group, while the placebo group had a 31.4% increase in AKs (P=0.0026). On final self-assessment, 85% of subjects reported being at least "satisfied" with the ability of the medication to decrease their AK burden. No side effects were reported. CONCLUSION: These results suggest that topical DNA repair enzymes may help reduce the number of AKs in individuals with moderate-to-severe photodamaged skin. Additionally, there may be a lasting effect of the DNA repair if application is discontinued. Further, cutaneous malignancies were not detected in any of the subjects during the study period. Despite the brevity of the study, these preliminary results suggest the role of DNA repair enzymes for not only treatment, but also skin cancer prevention. Further study and more objective evaluation measures are required for definitive conclusions to be drawn.

J Drugs Dermatol. 2017;16(10):1030-1034.

DNA repair enzymes: an important role in skin cancer prevention and reversal of photodamage--a review of the literature.

The incidence of skin cancer continues to increase annually despite preventative measures. Non-melanoma skin cancer affects more than 1,000,000 people in the United States every year.1 The current preventative measures, such as sunscreens and topical antioxidants, have not shown to be effective in blocking the effects of UV radiation based on these statistics. The level of antioxidants contained in the majority of skin creams is not sufficient to majorly impact free radical damage. Sunscreens absorb only a portion of UV radiation and often are not photostable. In this review article, we present the novel use of exogenous DNA repair enzymes and describe their role in combating photocarcinogenesis and photoaging. Topical application of these enzymes serves to supplement intrinsic DNA repair mechanisms. The direct repair of DNA damage by endogenous repair enzymes lessens rates of mutagenesis and strengthens the immune response to tumor cells. However, these innate mechanisms are not 100% efficient. The use of exogenous DNA repair enzymes presents a novel way to supplement intrinsic mechanisms and improve their efficacy. Several DNA repair enzymes critical to the prevention of cutaneous malignancies have been isolated and added to topical preparations designed for skin cancer prevention. These DNA repair enzymes maximize the rate of DNA repair and provide a more efficient response to carcinogenesis.

An experimental double-blind irradiation study of a novel topical product (TPF 50) compared to other topical products with DNA repair enzymes, antioxidants, and growth factors with sunscreens: implications for preventing skin aging and cancer.

The exposure to ultraviolet radiation (UVR) is a major risk factor for skin aging and the development of non-melanoma skin cancer (NMSC). Although traditional sunscreens remain the mainstay for the prevention of UVR-induced skin damage, they cannot ensure a complete protection against the whole spectrum of molecular lesions associated with UVR exposure. The formation of helix-distorting photoproducts such as cyclobutane pyrimidine dimers (CPD), as well as oxidative damage to DNA bases, including the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8OHdG) are among the key DNA lesions associated with photoaging and tumorigenesis. Besides DNA lesions, UVR-induced formation of free radicals can result in protein carbonylation (PC), a major form of irreversible protein damage that inactivates their biological function. This study compares a complex novel topical product (TPF50) consisting of three actives, ie, 1) traditional physical sunscreens (SPF 50), 2) a liposome-encapsulated DNA repair enzymes complex (photolyase, endonuclease, and 8-oxoguanine glycosylase [OGG1]), and 3) a potent antioxidant complex (carnosine, arazine, ergothionine) to existing products. Specifically, we assessed the ability of TFP50 vs those of DNA repair and antioxidant and growth factor topical products used with SPF 50 sunscreens in preventing CPD, 8OHdG, and PC formation in human skin biopsies after experimental irradiations. In head-to-head comparison studies, TPF50 showed the best efficacy in reducing all of the three molecular markers. The results indicated that the three TPF50 components had a synergistic effect in reducing CPD and PC, but not 8OHdG. Taken together, our results indicate that TPF50 improves the genomic and proteomic integrity of skin cells after repeated exposure to UVR, ultimately reducing the risk of skin aging and NMSC.

Topical application of preparations containing DNA repair enzymes prevents ultraviolet-induced telomere shortening and c-FOS proto-oncogene hyperexpression in human skin: an experimental pilot study.

The exposure to ultraviolet radiation (UVR) is one of the most important risk factors for skin aging and increases the risk of malignant transformation. Telomere shortening and an altered expression of the proto-oncogene c-FOS are among the key molecular mechanisms associated with photoaging and tumorigenesis. Photolyase from A. nidulans and endonuclease from M. luteus are xenogenic DNA repair enzymes which can reverse the molecular events associated with skin aging and carcinogenosis caused by UVR exposure. Therefore, the purpose of this study was to investigate whether the topical application of preparations containing DNA repair enzymes may prevent UVR-induced acute telomere shortening and FOS gene hyperexpression in human skin biopsies. Twelve volunteers (Fitzpatrick skin types I and II) were enrolled for this experimental study, and six circular areas (10 mm diameter) were marked out on the nonexposed lower back of each participant. One site was left untreated (site 1: negative control), whereas the remaining five sites (designated sites 2-6) were exposed to solar-simulated UVR at 3 times the MED on four consecutive days. Site 2 received UVR only (site 2: positive control), whereas the following products were applied to sites 3-6, respectively: vehicle (moisturizer base cream; applied both 30 minutes before and immediately after each irradiation; site 3); a traditional sunscreen (SS, SPF 50) 30 minutes before irradiation and a vehicle immediately after irradiation (site 4); a SS 30 minutes before irradiation and an endonuclease preparation immediately after irradiation (site 5); a SS plus photolyase 30 minutes before irradiation and an endonuclease preparation immediately after irradiation (site 6). Skin biopsies were taken 24 h after the last irradiation. The degree of telomere shortening and c-FOS gene expression were measured in all specimens. Strikingly, the combined use of a SS plus photolyase 30 minutes before irradiation and an endonuclease preparation immediately after irradiation completely abrogated telomere shortening and c-FOS gene hyperexpression induced by the experimental irradiations. We conclude that the topical application of preparations containing both photolyase from A. nidulans and endonuclease from M. luteus may be clinically useful to prevent skin aging and carcinogenesis by abrogating UVR-induced telomere shortening and c-FOS gene hyperexpression.

Reduced number of actinic keratoses with topical application of DNA repair enzyme creams.

BACKGROUND: Actinic keratosis is regarded as a carcinoma in situ by some dermatologists and its incidence continues to rise. Exposure to ultraviolet (UV) radiation is considered to be an important risk factor for developing these pre-malignant lesions. DNA repair enzymes have been shown to reverse sun-damage, resulting in reduced rates of actinic keratoses and non-melanoma skin cancers in specific patient populations. METHODS: Seventeen patients were evaluated for differences in actinic keratoses following topical application of T4N5 liposome lotion over 48 weeks. RESULTS: Compared to baseline, a statistically significant reduction in the number of actinic keratoses was seen following the treatment period. DISCUSSION: This study suggests that DNA repair enzyme creams effectively reduce the number of actinic keratoses in normal individuals with moderate-to-severe photodamaged skin.

Non-sunscreen photoprotection: antioxidants add value to a sunscreen.

The association between ultraviolet radiation (UVR) exposure and both skin cancer and photo-aging is well documented. In addition to the conventional organic-chemical and physical-mineral type sunscreens, other non-sunscreen protective strategies have been developed. These include topically applied botanical extracts and other antioxidants as well as topical DNA repair enzymes. Standard terms of photoprotection such as sun protection factor (SPF) do not accurately reflect the photoprotection benefits of these materials. For example, in spite of minimal SPF, tea extract containing polyphenols such as (-)-epigallocatechin-3-gallate (EGCG) has been shown to protect against UV-induced DNA damage and immune suppression, in part through its ability to reduce oxidative stress and inhibit NF-kB. The addition of botanical antioxidants and vitamins C and E to a broad-spectrum sunscreen may further decrease UV-induced damage compared with sunscreen alone. These agents have been shown to enhance protection against UV-induced epidermal thickening, overexpression of MMP-1and MMP-9, and depletion of CD1a(+) Langerhans cells. Non-sunscreen materials such as botanical extracts, antioxidants, and DNA repair enzymes can contribute value when applied topically to human skin in vivo.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 56-59; doi:10.1038/jidsymp.2009.14.

Modulation of UVB-induced Carcinogenesis by Activation of Alternative DNA Repair Pathways.

The molecular basis for ultraviolet (UV) light-induced nonmelanoma and melanoma skin cancers centers on cumulative genomic instability caused by inefficient DNA repair of dipyrimidine photoproducts. Inefficient DNA repair and subsequent translesion replication past these DNA lesions generate distinct molecular signatures of tandem CC to TT and C to T transitions at dipyrimidine sites. Since previous efforts to develop experimental strategies to enhance the repair capacity of basal keratinocytes have been limited, we have engineered the N-terminally truncated form (Δ228) UV endonuclease (UVDE) from Schizosaccharomyces pombe to include a TAT cell-penetrating peptide sequence with or without a nuclear localization signal (NLS): UVDE-TAT and UVDE-NLS-TAT. Further, a NLS was engineered onto a pyrimidine dimer glycosylase from Paramecium bursaria chlorella virus-1 (cv-pdg-NLS). Purified enzymes were encapsulated into liposomes and topically delivered to the dorsal surface of SKH1 hairless mice in a UVB-induced carcinogenesis study. Total tumor burden was significantly reduced in mice receiving either UVDE-TAT or UVDE-NLS-TAT versus control empty liposomes and time to death was significantly reduced with the UVDE-NLS-TAT. These data suggest that efficient delivery of exogenous enzymes for the initiation of repair of UVB-induced DNA damage may protect from UVB induction of squamous and basal cell carcinomas.

On the search for skin gene therapy strategies of xeroderma pigmentosum disease.

The introduction of genes through the skin has been an attractive and dynamic field of research in recent years. It gives the first gleam of hope in therapy for the human genetic diseases that mainly affect this tissue, such as patients that suffer from xeroderma pigmentosum, and who experience increased frequency of skin cancer. The first in vitro experiments were successful in correcting the genetic defects of cells from these patients, the ex vivo reconstruction of corrected cells has been achieved, and the skin of model animals has been treated resulting in cancer prevention. Up to now these efforts have been possible, thanks to the high efficiency of viral vectors that provide gene delivery and expression targeted to many of the different skin cells, including those with proliferative and pluripotent features, such as keratinocytes and epidermal cells of hair follicles. Moreover, progress with several other methodologies qualifies them as alternatives to be explored, in some cases in combination with viral vectors, for skin gene therapy in these patients. Exciting and encouraging new approaches promise benefits to xeroderma pigmentosum patients and their families, and open perspectives of new ways for interfering in gene driven metabolism in the skin.

Immune protective effect of a moisturizer with DNA repair ingredients.

Ultraviolet (UV) light damages DNA and impairs immune surveillance. The faulty repair of DNA after UV exposure is associated with immune suppression and facilitates photodamage that leads to photoaged skin and the growth of skin cancer. Sunscreens have been developed to filter UV light from entering the skin, but are not beneficial once DNA damage has occurred. Enhancing DNA repair after UV radiation may provide added advantage and prevent UV immunosuppression. This study was performed to determine whether a product with DNA repair ingredients prevents UV-induced suppression of contact hypersensitivity responses in vivo. Solar simulated radiation was delivered on skin with and without topical treatment with a moisturizer containing DNA repair enzymes (Advanced Night Repair Concentrate). Subjects were then sensitized to the hapten dinitrochlorobenzene, and the level of resultant contact hypersensitivity response was elicited 2 weeks later. Contact hypersensitivity response measured by skin fold thickness was significantly suppressed in untreated UV-irradiated subjects but not in subjects treated with DNA repair moisturizer after solar simulated radiation. Our results indicate that DNA repair ingredients significantly prevent UV-induced immune suppression.