Diona L. Damian

A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention

BACKGROUND Nonmelanoma skin cancers, such as basal-cell carcinoma and squamous-cell carcinoma, are common cancers that are caused principally by ultraviolet (UV) radiation. Nicotinamide (vitamin B3) has been shown to have protective effects against damage caused by UV radiation and to reduce the rate of new premalignant actinic keratoses. METHODS In this phase 3, double-blind, randomized, controlled trial, we randomly assigned, in a 1:1 ratio, 386 participants who had had at least two nonmelanoma skin cancers in the previous 5 years to receive 500 mg of nicotinamide twice daily or placebo for 12 months. Participants were evaluated by dermatologists at 3-month intervals for 18 months. The primary end point was the number of new nonmelanoma skin cancers (i.e., basal-cell carcinomas plus squamous-cell carcinomas) during the 12-month intervention period. Secondary end points included the number of new squamous-cell carcinomas and basal-cell carcinomas and the number of actinic keratoses during the 12-month intervention period, the number of nonmelanoma skin cancers in the 6-month postintervention period, and the safety of nicotinamide. RESULTS At 12 months, the rate of new nonmelanoma skin cancers was lower by 23% (95% confidence interval [CI], 4 to 38) in the nicotinamide group than in the placebo group (P=0.02). Similar differences were found between the nicotinamide group and the placebo group with respect to new basal-cell carcinomas (20% [95% CI, -6 to 39] lower rate with nicotinamide, P=0.12) and new squamous-cell carcinomas (30% [95% CI, 0 to 51] lower rate, P=0.05). The number of actinic keratoses was 11% lower in the nicotinamide group than in the placebo group at 3 months (P=0.01), 14% lower at 6 months (P<0.001), 20% lower at 9 months (P<0.001), and 13% lower at 12 months (P=0.001). No noteworthy between-group differences were found with respect to the number or types of adverse events during the 12-month intervention period, and there was no evidence of benefit after nicotinamide was discontinued. CONCLUSIONS Oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients. (Funded by the National Health and Medical Research Council; ONTRAC Australian New Zealand Clinical Trials Registry number, ACTRN12612000625875.).

Letters to patients: improving communication in cancer care

Numerous studies have shown that patients are usually dissatisfied with the information they receive during clinical consultations with medical specialists. Therefore, a randomised study design has been used to assess the role of personal letters to patients outlining their cancer consultation. Compared with the control group, patients receiving letters were more satisfied with the amount of information given, and tended to have greater and more accurate recall of the consultation. A survey of referring doctors revealed general support for the idea of sending to cancer patients letters that outline the substance of their consultations. The study shows that letters to patients are a useful method of improving patient satisfaction and recall in clinical consultations. They also provide a permanent record of the consultation, which can be kept for future reference, and encourage greater patient involvement in their care.

Role of Nicotinamide in DNA Damage, Mutagenesis, and DNA Repair

Nicotinamide is a water-soluble amide form of niacin (nicotinic acid or vitamin B3). Both niacin and nicotinamide are widely available in plant and animal foods, and niacin can also be endogenously synthesized in the liver from dietary tryptophan. Nicotinamide is also commercially available in vitamin supplements and in a range of cosmetic, hair, and skin preparations. Nicotinamide is the primary precursor of nicotinamide adenine dinucleotide (NAD+), an essential coenzyme in ATP production and the sole substrate of the nuclear enzyme poly-ADP-ribose polymerase-1 (PARP-1). Numerous in vitro and in vivo studies have clearly shown that PARP-1 and NAD+ status influence cellular responses to genotoxicity which can lead to mutagenesis and cancer formation. This paper will examine the role of nicotinamide in the protection from carcinogenesis, DNA repair, and maintenance of genomic stability.

An action spectrum for ultraviolet radiation‐induced immunosuppression in humans

Background  The immune‐suppressive effects of sunlight play a central role in skin carcinogenesis. Ultraviolet (UV) B radiation is highly immunosuppressive even at suberythemal doses, and longwave UVA is now also recognized to cause immunosuppression in humans. The relative contributions of UVA and UVB to immunosuppression by incidental daily sun exposure are, however, unclear.

Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans

Cutaneous immunity, which is a key defence against the development of skin cancers, is suppressed by even small doses of ultraviolet (UV) radiation. Preventing this UV-induced immunosuppression may therefore reduce the incidence of skin cancer. Nicotinamide (vitamin B3) has immune-protective and cancer-preventive effects against UV radiation in mice, and we have shown previously that topical nicotinamide is immune protective in humans. Using the Mantoux model of skin immunity in healthy volunteers, we compared oral nicotinamide to placebo (both administered for 1 week) in a randomized, double-blinded, crossover design against the effects of solar-simulated ultraviolet (ssUV) radiation on delayed-type hypersensitivity to tuberculin purified protein derivative. Discrete areas of the back were irradiated with low doses of ssUV daily for three consecutive days. Immunosuppression, calculated as the difference in Mantoux-induced erythema of irradiated sites compared with unirradiated control sites, was determined in volunteers taking oral nicotinamide and placebo. Significant immunosuppression occurred in an UV dose-dependent manner in the presence of placebo. Oral nicotinamide, at doses of either 1500 or 500 mg daily, was well tolerated and significantly reduced UV immunosuppression with no immune effects in unirradiated skin. Oral nicotinamide is safe and inexpensive and looks promising as a chemopreventive supplement for reducing the immunosuppressive effects of sunlight.

Topical calcitriol protects from UV‐induced genetic damage but suppresses cutaneous immunity in humans

Please cite this paper as: Topical calcitriol protects from UV‐induced genetic damage but suppresses cutaneous immunity in humans. Experimental Dermatology 2010; 19: e23‐e30.

Non-melanoma skin cancer: carcinogenesis and chemoprevention

Summary Non-melanoma skin cancer (NMSC) is by far the most frequently diagnosed cancer in Australia, and exposure to ultraviolet (UV) radiation is the primary cause. Both UVB and UVA radiation have been shown to cause DNA damage and immunosuppression, the important forms of biological damage that lead to NMSC. The DNA of keratinocytes absorbs UV radiation and produces photolesions such as cyclobutane pyrimidine dimers (CPDs). UV absorption by other chromophores results in the production of reactive oxygen species which cause oxidative damage to DNA such as 8-oxo-7,8-dihydroguanine (8oxoG). These photolesions can then, if not correctly repaired, lead to signature mutations. Reactive oxygen species also cause receptor activation and damage lipids and proteins. UV also deprives cells of adenosine triphosphate, and causes inflammation and cell cycle dysregulation. UV radiation has been shown to exert potent immunosuppressive effects on the skin through a number of molecular and cellular mechanisms. Many tumour suppressor genes and oncogenes have been studied and implicated in photocarcinogenesis, particularly p53, PTCH1, BRM and RAS. Clinical observations, histological analysis, as well as molecular and cytogenetic studies have shown actinic keratoses (AKs) and Bowens disease (BD) to be precursors of squamous cell carcinomas (SCCs). Keratoacanthomas (KAs), a type of SCC, and AKs have frequently been observed to regress. Sun protective measures and sunscreens can reduce the incidence of NMSCs, although their effectiveness is limited by non-compliance. A large number of chemopreventive agents have been investigated, but to date none has been found to be clinically useful except within selected high risk groups. Therefore, further research is urgently required to find an ideal chemopreventive agent that is effective, safe, accessible and convenient.

Ultraviolet A radiation: its role in immunosuppression and carcinogenesis.

Ultraviolet A (UVA) radiation is immunosuppressive and mutagenic in humans and carcinogenic in animals. UVA suppresses immunity with a bell-shaped dose response. At doses equivalent to 15-20 minutes of sun exposure at noon, UVA contributes to approximately 75% of sunlight-induced immunosuppression. A recent action spectrum, indicating that 360-380 nm but not 320-350 nm UVA suppresses immunity in humans, suggests an important role for reactive oxygen species. UVA also causes an energy crisis in cells, and normalization of adenosine triphosphate with nicotinamide prevents UVA immunosuppression. UVA activation of the alternative complement pathway and defects in memory T-cell development are also involved. Human skin cancers contain mutations in the p53 and BRM genes that are consistent with being induced by UVA. UVA is also mutagenic in human skin equivalents. The basal layer of human skin is more susceptible to UVA-induced mutations than the upper layers. Because skin cancers arise from these basal proliferating cells, this finding is likely to be important and could be attributable to low levels of the DNA repair enzyme OGG1 in basal cells. UVA is therefore likely to make a larger contribution to UVA-induced skin carcinogenesis in humans than is predicted by small animal models as the result of being immunosuppressive and mutagenic for basal keratinocytes.

Oral Nicotinamide Reduces Actinic Keratoses in Phase II Double-Blinded Randomized Controlled Trials

TO THE EDITOR Nicotinamide (vitamin B3) prevents photocarcinogenesis in mice (Gensler et al., 1999) and photoimmunosuppression in humans (Damian, 2010). Actinic keratoses (AKs) strongly predict nonmelanoma skin cancer risk (Green and Battistutta, 1990). These phase II studies aimed to determine whether oral nicotinamide, at different doses, reduced AKs in sun-damaged individuals. Healthy, immune-competent volunteers with X4 palpable AKs (face, scalp and upper limbs) were recruited from Royal Prince Alfred Hospital Dermatology Clinics, Sydney, Australia. The study protocols (ACTRN12609000490279; ACTRN12610000689077; http://www. anzctr.org.au) adhered to Helsinki Guidelines and were approved by the Sydney South West Area Health Service and University of Sydney ethics committees. All volunteers provided written informed consent. Participants were randomly assigned (1:1) to take nicotinamide 500 mg (Nature’s Own, Virginia, Queensland, Australia) or matched placebo (Australian Custom Pharmaceuticals, Sydney, New South Wales, Australia) twice daily (Study 1) or once daily (Study 2) for 4 months. The treatment allocation sequence was determined by a computergenerated randomization list prepared using a permuted blocks method (block size 6) by an investigator (DLD) not involved in AK assessment. Participants underwent complete skin examination before randomization, were encouraged to use daily sunscreen, and remained blinded throughout the study. At baseline, 2 and 4 months, palpable AKs were identified visually and by touch by a blinded observer (DS), counted and documented on a body grid chart. At baseline and 2 months, full blood count, creatinine, and liver function were assessed. A target of 36 patients was selected for Study 1 based on clinical judgement as this was our first pilot trial of oral nicotinamide. A conservative

Topical nicotinamide modulates cellular energy metabolism and provides broad-spectrum protection against ultraviolet radiation-induced immunosuppression in humans

Background  Ultraviolet (UV) radiation can profoundly suppress the cutaneous immune system, thus enhancing carcinogenesis. Agents that prevent UV‐induced immunosuppression may thus reduce skin cancer. Nicotinamide (vitamin B3) prevents UV‐induced immunosuppression and carcinogenesis in mice, and solar‐simulated (ss) UV‐induced immunosuppression in humans. Its effectiveness against different UV wavebands and mechanism of action is as yet unknown.