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Purpose: Previously, we reported the results of a Phase III, placebo-controlled trial in 2,297 randomized participants with moderately severe actinic keratoses wherein 25,000 IU/ day vitamin A caused a 32% risk reduction in squamous cell skin cancers. We hypothesized that dose escalation of vitamin A to 50,000 or 75,000 IU/day would be both safe and more efficacious in skin cancer chemoprevention.Experimental Design: One hundred and twenty-nine participants with severely sun-damaged skin on their lateral forearms were randomized to receive placebo or 25,000, 50,000, or 75,000 IU/day vitamin A for 12 months. The primary study end points were the clinical and laboratory safety of vitamin A, and the secondary end points included quantitative, karyometric image analysis and assessment of retinoid and rexinoid receptors in sundamaged skin.Results: There were no significant differences in expected clinical and laboratory toxicities between the groups of participants randomized to placebo, 25,000 IU/day, 50,000 IU/day, and 75,000 IU/day. Karyometric features were computed from the basal cell layer of skin biopsies, and a total of 22,600 nuclei from 113 participants were examined, showing statistically significant, dose-response effects for vitamin A at the 25,000 and 50,000 IU/day doses. These karyometric changes correlated with increases in retinoic acid receptor ␣, retinoic acid receptor ␤, and retinoid X receptor ␣ at the 50,000 IU/day vitamin A dose.Conclusions: The vitamin A doses of 50,000 and 75,000 IU/day for 1 year proved safe and equally more efficacious than the 25,000 IU/day dose and can be recommended for future skin cancer chemoprevention studies.

Objectives: To explore p53 and proliferating cell nuclear antigen (PCNA) expression and polyamine content as biomarkers in skin cancer chemoprevention trials, we evaluated their expression in early stages of UV-induced squamous cell tumorigenesis. Methods: Biopsies were collected from three groups: 78 subjects with sun damage on forearms, 33 with actinic keratosis (AK) on forearms, and 32 with previous squamous cell carcinoma. Participants with sun damage were randomized to sunscreen or no sunscreen. Results: We found significant differences in p53 and polyamines in forearms from the sun-damaged group (11.5 F 1.2% for p53, 65.5 F 1.9 nmol/g for putrescine, and 187.7 F 3.3 nmol/g for spermidine) compared with the group with sun damage plus AK (20.9 F 2.3% for p53, P = 0.0001; 81.7 F 3.9 nmol/g for putrescine, P = 0.0001; 209.4 F 8.2 nmol/g for spermidine, P < 0.06). PCNA was not different. When lesion histology was considered, there was a stepwise significant increase in p53 in biopsies without characteristics of AK compared with early AK (P = 0.02) and AK (P = 0.0006) and a similar pattern for PCNA with the only significant difference between early AK and AK. There was a stepwise increase in putrescine and spermidine in normal, sun-damaged forearm, forearm from subjects with AK, and the AK lesion itself (P < 0.0001). No significant differences in p53 or polyamines were seen in 3-month biopsies or, as a result of sunscreen use, although PCNA in the sun-damaged group not using sunscreen decreased significantly. Conclusions: p53 expression and polyamines in skin were elevated in early stages of skin tumorigenesis and were not affected by sunscreen, adding validity to their use as biomarkers in skin cancer chemoprevention trials. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1841 -8)

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Prior research shows that topical application of free, non-fatty acid conjugated vitamin E (dl-α-tocopherol) prevents skin cancer in mice, as well as immunosuppression induced by UVB radiation (Nutr. Cancer 26, 183–191, 1996). This study investigated the chemopreventive potential of dl-α-tocopherol in humans through monitoring surrogate endpoint biomarkers in sun-damaged skin. Methods Contralateral arms of healthy human volunteers with actinic keratoses (AKs) were randomly assigned to receive either 12.5% dl-α-tocopherol or placebo in a crème base for 6 months. Changes in number of AKs, levels of p53 protein expression, proliferating cell nuclear antigen (PCNA) and polyamines were assessed along with skin and systemic vitamin E levels. Results Following treatment, plasma concentration levels of dl-α-tocopherol were unchanged, but skin levels were highly elevated (p<0.001). Levels of p53 and PCNA did not change significantly while number of AKs declined insignificantly in both placebo and treatment arms. Regression models demonstrated significant decreases in putrescine, spermidine, spermine, and total polyamine concentrations following treatment. Discussion Topically applied dl-α-tocopherol was substantially absorbed in skin, but the 6-month application did not significantly reduce numbers of pre-existing AKs on moderately to severely sun-damaged forearms. Increases in polyamine synthesis are expected during tumor initiation and promotion; conversely, the significant reductions in polyamine levels resulting from the topical dl-α-tocopherol application are consistent with reductions in tumorigenesis potential. Topical tocopherol did not normalize established sun-induced lesions, but dl-α-tocopherol induced reductions in polyamine metabolism are consistent with the inhibition of skin squamous cell carcinogenesis as seen in previous human trials and animal models.