Chemoprevention of Human Actinic Keratoses by Topical dl-α-tocopherol

Abstract

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.

Skin Carcinogenesis Studies Using Mouse Models with Altered Polyamines

“… 168 , 169 The topical administration of DFMO to patients with existing AKs also significantly reduced the number of lesions. 170 , 171 The strong chemopreventive effects of DFMO, along with minimal toxicity, reinforce the idea that polyamines are more essential for the growth and survival of tumor cells than their normal counterparts. These data support the use of DFMO as a chemopreventive agent for NMSC and underscore the relevance of the polyamine pathway in skin tumor development.…”

Cancer Chemoprevention: A Strategic Approach Using Phytochemicals

“…The results showed no significant decrease in the number of AKs, expression of PCNA and p53; however, the level of polyamines was relatively low in the treated group. Though the authors of the study considers reduction of polyamines as a positive indicator of its chemopreventive potential in clinic, this effect could be outweighed by the unchanged expression status of p53 and PCNA ( Foote et al, 2009 ). Hence, this warrants further trials using incidence of NMSC as the end point.…”

Chemoprevention of Keratinocyte Carcinomas: An Updated Review

“…However, a reduction in polyamine levels in the skin was noted [41]. The instability of vitamin E on the skin may contribute to conflicting results in clinical trials.…”