Topical pimecrolimus and tacrolimus do not accelerate photocarcinogenesis in hairless mice after UVA or simulated solar radiation

Abstract

Pimecrolimus and tacrolimus are topical calcineurin inhibitors developed specifically for the treatment of atopic eczema. Experience with long-term use of topical calcineurin inhibitors is limited and the risk of rare but serious adverse events remains a concern. We have previously demonstrated the absence of carcinogenic effect of tacrolimus alone and in combination with simulated solar radiation (SSR) on hairless mice. The aim of this study is to determine whether pimecrolimus accelerates photocarcinogenesis in combination with SSR or pimecrolimus and tacrolimus accelerate photocarcinogenesis in combination with UVA. We used 11 groups of 25 hairless female C3.Cg/TifBomTac immunocompetent mice (n = 275). Pimecrolimus cream or tacrolimus ointment was applied on their dorsal skin three times weekly followed by SSR (2, 4, or 6 standard erythema doses, SED) or UVA (25 J/cm(2)) 3-4 h later. This was done up to 365 days in the SSR-treated groups and up to 500 days in the UVA-treated groups. Pimecrolimus did not accelerate the time for development of the first, second or third tumor in any of the groups. Median time to the first tumor was 240 days for the control-2SED group compared with pimecrolimus-2SED group (233 days), control-4SED group (156 days) compared with pimecrolimus-4SED group (163 days) and control-6SED group (162 days) compared with pimecrolimus-6SED group (170 days). Only one mouse in each of the three UVA groups developed a tumor. We conclude that pimecrolimus in combination with SSR and both pimecrolimus and tacrolimus in combination with UVA do not accelerate photocarcinogenesis in hairless mice.

Topical hydrocortisone, clobetasol propionate, and calcipotriol do not increase photocarcinogenesis induced by simulated solar irradiation in hairless mice

“…1), calcineurin inhibitors do not carry the risk of local side effects such as skin atrophy, striae, and acne (3,23–25). Previously, we demonstrated that hairless mice exposed to calcineurin inhibitors in combination with SSR do not have accelerated photocarcinogenesis (13,15).…”

Neonatal mice do not have increased sensitivity to induction of squamous cell carcinomas

“…A study found SCC to be most efficiently induced by chronic low‐dose exposure and neonatal and intermittent exposure favoured papilloma development over SCCs . We have previously demonstrated in our animal model that UVB is a more effective inducer of SCC than UVA . It has also been demonstrated that neonates can survive a very high UVR dose possibly because their immune system is not fully developed .…”

Topical tacrolimus treatment does not facilitate photocarcinogenesis in cancer-prone mice

“…Topical application of tacrolimus shows therapeutic effect on inflammatory skin diseases such as atopic dermatitis [1]. Recent studies demonstrated that topical pimecrolimus and tacrolimus did not accelerate photocarcinogenesis in hairless mice after UVA or simulated solar radiation [3,4]. Recent studies demonstrated that topical pimecrolimus and tacrolimus did not accelerate photocarcinogenesis in hairless mice after UVA or simulated solar radiation [3,4].…”