# Role of Nicotinamide in Genomic Stability and Skin Cancer Chemoprevention
## 5 NAD+ Status and Skin Cancer
### NAM and Chemoprevention  
Oral NAM at doses of 500 mg twice daily and 500 mg once daily was evaluated in two double-blind, randomized, placebo-controlled phase two trials in Australians with sun-damaged skin with an average of more than 30 AK at baseline. Within four months, significant relative reductions in AK of 35% and 29% with twice daily and once daily NAM dosing have been observed, respectively [87]. A phase three randomized controlled trial was carried out on 386 Australians that had had at least two non-melanoma skin cancers (NMSC) in the previous five years. The study showed that oral NAM treatment (500 mg twice daily for 12 months) is safe and effective in reducing the rates of new NMSCs and AKs. Patients receiving NAM showed a 23% relative rate reduction in new NMSCs (basal cell carcinoma (BCC) and SCC) compared to placebo (\(p=0.02\)); the unadjusted relative rate reduction was 27% (\(p=0.02\)). There were similar magnitudes of reduction for both BCC (relative rate reduction 20%, \(p=0.12\)) and SCC (relative rate reduction 30%, \(p=0.05\)). No difference in NAM effectiveness in reducing cSCC in situ versus well-differentiated and versus moderately-differentiated was observed [88]. Notably, a significant decrease in the number of macrophages was observed in those lesions arising in NAM treated-patients compared to placebo [89]. AK counts followed the same trend. Significant relative reductions in AK counts were observed throughout the intervention period at three, six, nine, and 12 months. NAM effectiveness in reducing AK counts appeared to plateau after the nine-month visit (relative rate reduction 20%, \(p<0.001\)). However, there is no evidence of benefit after NAM is discontinued [88]. Any significant effects of oral NAM on cognitive function nor on quality of life have been found [90]. Two small phase two randomized controlled trials indicated that NAM may also have chemoprotective effects in immune-suppressed transplant recipients. Thirty renal transplant recipients received placebo or nicotinamide 250 mg thrice daily for six months and found reductions in AKwithout detectable effects on the blood levels of immune-suppressed patients [91]. Twenty-two renal transplant recipients were treated with placebo or NAM 500 mg twice daily for six months and found non-significant trends to reduction in new skin cancers and AK over the six-month intervention period without significant increase in adverse effects nor significant change in blood or urine parameters or blood pressure [92]. Unlike NA, oral NAM does not cause vasodilatory side-effects, such as flushing, headache, hypotension, and itch, and has been well tolerated at high doses (1.5-3 g daily) for a range of clinical and research indications including inflammatory skin diseases [93], as a radio-sensitizer [94], and in diabetes prevention studies in children and adults [95]. NAM has an established safety profile even at high doses, although a reversible elevation of liver enzymes and nausea have been reported in some patients at much higher daily doses (8 g daily) [1]. The phase three clinical trial included patients ranging in age from 30 to 91 years (mean 66 years), many with multiple comorbidities and receiving numerous concurrent medications [88]. The 86 serious adverse event reports, were evenly distributed across the placebo and NAM arms, with no notable between-group differences in adverse events nor in blood pressure or bodyweight (measured quarterly for 12 months), full blood count, renal function, or hepatic function (measured at baseline and at 12 months) [88]. Systemic absorption of topically delivered NAM has been reported to be approximately 10% depending on the vehicle used [96]. NA and its derivatives applied topically may act also through the nicotinic acid receptor signaling inducing keratinocyte differentiation [3]. NAM inhibits phosphate co-transport in the gut and in the renal proximal tubule, and it has been used as a phosphate-lowering agent in hemodialysis patients, at doses of 1-2 g daily [97].