| dcterms.abstract | Actinic keratosis (AK), a cutaneous lesion resulting from the proliferation of atypical epidermal keratinocytes, has an incidence of 11%-26% and its prevalence is 58 million in the US alone. AK is a precursor to non-melanoma skin cancer (NMSC). NMSC, consisting of squamous cell and basal cell carcinomas, represents the most frequent human cancer. Current treatment for AK and NMSC is often limited by low efficacy, side effects, high cost, and undesirable cosmetic outcomes. Thus new agents for the treatment of AK are urgently needed. In an effort to develop an efficacious, safe and patient-acceptable approach to both AK and NMSC, we developed a topically applicable drug combination consisting of the novel agent phospho-sulindac, a modified non-steroidal anti-inflammatory drug, and difluoromethylornithine an inhibitor of polyamine synthesis. The two agents were formulated in a pluronic lecithin organogel. After a systematic evaluation of penetration enhancers using in vitro dermal drug diffusion and in vivo pharmacokinetic studies, we developed an optimal formulation which we evaluated in vivo. For NMSC we used an intradermal A431 human skin cancer xenograft in nude mice that provides a therapeutic model for the topical application of test agents. For AK, we used the UV irradiation model that recapitulates many aspects of the injurious effect of solar radiation on the skin, the main cause of AK. The topical application of phospho-sulindac and difluoromethylornithine combination reduced NMSC by 71%. The effect was mediated in part through suppression of intracellular polyamine levels; polyamines control cell proliferation. The PS/DFMO topical application had remarkably strong effect on AK. PS/DFMO induced lesion regression evident in a few days (tumor volume 51% on day 7). By the end of the study (day 22), compared to time 0 values, the lesion volume/mouse was 62% lower and the lesion number/mouse was 70% lower. Importantly, 51% of the animals were lesion-free. Efficacy comparison to the widely used diclofenac gel 3% showed that after 15-days of treatment, diclofenac had no efficacy at all but significant side effects. No animal on PS/DFMO had any side effects, topical or systemic, from PS/DFMO. Mechanistically, PS/DFMO acts at least in part though polyamines and the cellular redox status. PS/DFMO reduced significantly polyamines in AK skin. Compared to normal mice never exposed to UV, AK mice had markedly elevated levels of urinary 15-Isoprostane F2t, a marker of oxidative stress. PS/DFMO eliminated the oxidative stress associated with AK. PS/DFMO is a promising topical drug combination of the treatment of NMSC and AK. | |
