Effect of 5-fluorouracil classical emulsion versus 5-fluorouracil manipulated in emulsion with hydrophilic polymer and high spreed homogenization on the cancerization field and advanced photoaging

Abstract

Photoaging or extrinsic aging represents the overlap of the biological effects of chronic and uncontrolled exposure to ultraviolet (UV) radiation A and B on chronological or intrinsic aging. The damage caused by UV radiation on various cellular structures leads to cutaneous morphological changes due to biomolecular modifications. Multiple actinic keratoses and cancerization field are signs of advanced photodamage, which are considered risk markers for the development of malignant lesions, especially squamous cell carcinoma. Topical use of 5-fluorouracil (5-FU) 5%, 1% and 0.5% cream is approved as a treatment for multiple actinic keratoses. However, its limitations of use are associated with side effects such as burning, erythema, peeling and pruritus. Currently, the development of topical medications employing new technologies, such as high spreed homogenization, aims at a better efficacy of formulations with fewer adverse events. Objectives: Primary: To evaluate the efficacy, safety and tolerability profile through the clinical, histological and immunohistochemical epidermal and dermal effects of 5% 5-FU on topical emulsion manipulated with high spreed homogenization compared to the traditional emulsion on the treatment of AKs and cancerization field on the forearms of immunocompetent patients; Secondary: 1) Investigate the pathways involved on the photoaging and cancerization field through the analysis of gene expression; 2) To compare the cellular and molecular pathways associated with extrinsic and intrinsic aging.Method: Study of therapeutic intervention, randomized, comparative, double-blind. After approval by the Research Ethics Committee - UNIFESP and signing of the Informed Consent Term (ICT), 41 participants who present severe or advanced photoaging on forearms will be included. Therapeutic regimens will comprise the use of 5-FU 5% traditional cream twice daily for four weeks on a forearm and 5-FU 5% emulsion manipulated with high spreed homogenization twice daily on the contralateral forearm, four weeks, defined by randomization (left and right), through a computer program. The evaluation of effectiveness will be made through the following parameters: 1. clinically, through the opinion of the patient, the investigator and two independent observers (dermatologists), by comparison of standardized photographs, using a validated scale of photoaging; 2. Non-invasive instrumental measures: 2.1. viscoelastic properties, 2.2 aqueous content of the stratum corneum and 2.3. Ultrasonography of high frequency that allows the visualization of the dermis and measurements of thickness and echogenicity. All measurements will be taken before, 4 and 12 weeks after the start of treatment; 3. Skin biopsies, at the same point marked for non-invasive measurements, before and 12 weeks after the start of treatment shall be performed on each forearm for histological and immunohistochemical examinations in order to evaluate epidermal and dermal aspects and analysis of gene expression by molecular biology. Before the beginning of the treatment, a biopsy will also be performed on the ventral region of the left arm, close to the elbow, for a comparative effect of a skin with less actinic damage, which would allow to evaluate which pathways would be activated associated with the extrinsic and intrinsic aging. The safety assessment will be based on the reporting and observation of adverse events. (AU)