Topical calcitriol prior to photodynamic therapy enhances treatment efficacy in non-melanoma skin cancer mouse models

Abstract

Non-melanoma skin cancers (NMSCs) such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common form of human cancer worldwide, and their incidence is increasing. Photodynamic therapy (PDT), mediated by topically applied aminolevulinic acid (ALA) and subsequent exposure to light (either a laser or a noncoherent source), is being increasingly used for the treatment of dermatological disorders, including BCC and SCC. However, therapeutic responses of NMSCs to ALA-PDT are currently not superior to standard therapies, although the latter have undesirable side effects including scarring. In this study, we report that preconditioning of skin tumors with calcitriol (active form of Vitamin D; Vit D) prior to ALA-PDT, significantly improves the treatment outcome. In BCC and UVB-induced SCC mouse models, we identified an increase in tumor-specific accumulation of ALA induced photosensitizer (protoporphyrin IX, PpIX) due to Vit D preconditioning, of up to 6-fold in vivo. In addition, increased expression of differentiation (145 fold, p < 0.02) and proliferation (42 fold, p < 0.005) markers were identified in BCC tumors, all leading to increased tumor destruction (18.3 fold, p < 0.03) with the combination approach, as compared to ALA-PDT alone. Histomorphological changes identified using hematoxylin and eosin staining, and results of TUNEL staining, together documented a beneficial effect of Vit D pretreatment upon tumor cell death. We conclude that this new combination approach with Vit D and ALA-PDT has great potential to achieve complete remission of NMSC tumors, with excellent cosmetic results and an overall beneficial impact upon patient care.

Defining the timing of 25(OH)D rescue following nitrogen mustard exposure

“…While other groups demonstrate that SM causes delayed wound formation 19 , our data in NM mouse model reveals that 25(OH)D delivered at either 1 h or up to 24 h post-exposure was sufficient to delay the appearance of erythema and skin wound suggesting that 25(OH)D may inhibit uncontrolled activation of first responder cells such as neutrophils and macrophages that exacerbate inflammation at the wound bed. Although pretreatment with oral and topical calcitriol used as combination therapy 20 has proven efficacy in diminishing incidence of breast cancer and severity of IBD 21 in mouse models, in our hands pretreatment with 25(OH)D did not improve wound healing. This may be due to 25(OH)D arrest of infiltrating activated cells to the wound bed, a key inflammatory event that precedes the differentiation of reparative macrophages and is critical to wound healing 22 .…”

A randomized split-scalp study comparing calcipotriol-assisted methyl aminolaevulinate photodynamic therapy (MAL-PDT) with conventional MAL-PDT for the treatment of actinic keratosis

“…The potential of topical vitamin D to enhance PpIX formation was previously demonstrated in a murine model of chemically induced SCC and basal cell carcinoma (BCC), leading to increased PpIX accumulation and enhanced apoptotic cell death in the vitamin D‐pretreated tumours . In addition, increased expression of cellular proliferation and differentiation markers was identified in these pretreated tumours .…”

“…The potential of topical vitamin D to enhance PpIX formation was previously demonstrated in a murine model of chemically induced SCC and basal cell carcinoma (BCC), leading to increased PpIX accumulation and enhanced apoptotic cell death in the vitamin D‐pretreated tumours . In addition, increased expression of cellular proliferation and differentiation markers was identified in these pretreated tumours . Nevertheless, in another animal study, a short‐term 3‐day pretreatment with calcipotriol, 5‐ fluorouracil and imiquimod before MAL‐PDT did not further delay tumour onset in ultraviolet (UV)‐exposed hairless mice …”

Noninvasive Optical Imaging of UV‐Induced Squamous Cell Carcinoma in Murine Skin: Studies of Early Tumor Development and Vitamin D Enhancement of Protoporphyrin IX Production

“…4c, weeks [14][15][16][17][18][19][20] are due to increased stratum corneum permeability alone, because the PpIX signal rapidly diminished after UV cessation (Fig. 4c, weeks [21][22][23][24]. Similarly, PpIX signals in AK/SCCbearing skin, which were higher after VD pretreatment than after vehicle pretreatment alone (Fig.…”

“…About a decade ago, in an attempt to find ways to increase PDT efficacy and thereby expand its usefulness, our laboratory embarked on a program to identify agents that could be combined with PDT to boost the accumulation of intratumoral PpIX, by increasing the activity of the mitochondrial heme synthesis pathway; reviewed by Anand et al (17). In preclinical mouse models and more recently in human patients, we have shown that preconditioning of tumors with certain protoporphyrin-enhancing agents, including methotrexate (18,19), 5-fluorouracil (20) and vitamin D (VD) (21)(22)(23)(24), markedly increases not only the tumor-specific accumulation of PpIX, but also the cytotoxic treatment effect once illumination is applied. Our previous studies employed skin biopsies and tumor sectioning to assess PpIX levels by biochemical and confocal fluorescence techniques.…”