Topical Calcineurin Inhibitors Decrease the Production of UVB-Induced Thymine Dimers from Hairless Mouse Epidermis

Abstract

Background: An increased incidence of ultraviolet-light-related skin tumours is a well-known problem in patients undergoing posttransplantation immunosuppression with systemic calcineurin inhibitors such as cyclosporine A or tacrolimus. UV-related carcinogenesis as a consequence of long-term treatment of sun-exposed sites with topical calcineurin inhibitors is therefore of theoretical concern. Results: In this study, we show that tacrolimus acts as a UVB filter when incorporated into liposome membranes. In hairless mice pretreated with 1% pimecrolimus cream, 0.1% tacrolimus ointment or vehicle, the amount of epidermal thymine dimers, measured 1 h after 1 J/cm² of UVB irradiation, was decreased by 89, 84 and 47%, respectively, as compared to untreated mice. Forty-eight hours after UVB irradiation, 97, 89 and 93% of epidermal thymine dimer levels were removed in pimecrolimus-, tacrolimus- or vehicle-treated mice, respectively. In contrast, 69% of thymine dimers, originally present in much higher amounts than in treated mice, were removed from untreated controls. UVB-induced apoptosis was less pronounced in treated mice. Conclusion: Taken together, these results suggest that topical calcineurin inhibitors prevent DNA photodamage due to a filter effect of both vehicle and active components, whereas they do not affect the clearance of DNA photoproducts.

Lack of Association between Exposure to Topical Calcineurin Inhibitors and Skin Cancer in Adults

“…However, some animal studies do demonstrate a decreased association between TCIs and skin cancer in photocarcinogenesis models [5, 15, 19]. Furthermore, several recent cell culture studies have demonstrated that many of the same cellular pathways found in lymphocytes are also found in keratinocytes, and that TCIs can inhibit the growth and differentiation of keratinocytes [18, 19,29,30,31,32,33,34]. Finally, it is very important to note that the use of these agents is very different in our population as compared to solid organ transplant patients.…”

“…Other investigators, using the same model but a different dosing protocol, observed that topical treatment with tacrolimus protected against tumor formation [15, 16]. In addition, models of UV-induced DNA damage may also indicate a protective effect from TCIs [17,18,19]. …”

Current Approach to Phototherapy Applications in Dermatology Practice: Part 2. Phototherapy in Vitiligo, Mycosis Fungoides, Atopic Dermatitis, Sclerosing Diseases and Psoriasis

“…Ancak, yapılan bir çalışmada, topikal takrolimus ve pimekrolimusun UV ile indüklenen timin dimerleri oluşumunu inhibe ettikleri gösterilmiştir (28). Yine de, uzun dönemde ortaya çıkabilecek yan etkileri tam olarak ekarte edebilmek için daha çok çalışmaya ihtiyaç olduğu, mevcut verilerle bu kombinasyonun rutin olarak önerilmemesi gerektiği vurgulanmaktadır (7).…”

Topical Calcineurin Inhibitors in the Treatment of Vitiligo

“…44 However, the results of a 2005 study on hairless mice suggest that topical tacrolimus prevents DNA photodamage due to a filter effect of both active and vehicle components in topical formulation but does not affect the clearance of DNA photoproducts. 45 Fai et. al., employed combined therapy, and indicated a rapid and relevant improvement of facial vitiligo, followed by lesions on the limbs and trunk (including the neck), whereas the overall response of vitiligo in other skin areas (extremities and genital areas) was poor.…”

“…al., employed combined therapy, and indicated a rapid and relevant improvement of facial vitiligo, followed by lesions on the limbs and trunk (including the neck), whereas the overall response of vitiligo in other skin areas (extremities and genital areas) was poor. 46 This fact has been attributed to the greater density of hair follicles in the head and neck areas, and thus, greater melanocyte reservoirs. 47 Further long-term efficacy and safety data and randomized controlled trials on a large number of study participants are required.…”