The Vitamin D Analog Calcipotriol Combined with Aminolevulinate‐Mediated Photodynamic Therapy for Human Psoriasis: A Proof‐of‐Principle Study

Abstract

We previously showed that select agents (methotrexate or Vitamin D), when administered as a preconditioning regimen, are capable of promoting cellular differentiation of epithelial cancer cells while simultaneously enhancing the efficacy of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT). In solid tumors, pretreatment with Vitamin D simultaneously promotes cellular differentiation and leads to selective accumulation of target porphyrins (mainly protoporphyrin IX, PpIX) within diseased tissue. However, questions of whether or not the effects upon cellular differentiation are inexorably linked to PpIX accumulation, and whether these effects might occur in hyperproliferative noncancerous tissues, have remained unanswered. In this paper, we reasoned that psoriasis, a human skin disease in which abnormal cellular proliferation and differentiation plays a major role, could serve as a useful model to test the effects of pro-differentiating agents upon PpIX levels in a non-neoplastic setting. In particular, Vitamin D, a treatment for psoriasis that restores (increases) differentiation, might increase PpIX levels in psoriatic lesions and facilitate their responsiveness to ALA-PDT. This concept was tested in a pilot study of 7 patients with bilaterally-matched psoriatic plaques. A regimen in which calcipotriol 0.005% ointment was applied for 3 days prior to ALA-PDT with blue light, led to preferential increases in PpIX (~130%), and reductions in thickness, redness, scaling, and itching in the pretreated plaques. The results suggest that a larger clinical trial is warranted to confirm a role for combination treatments with Vitamin D and ALA-PDT for psoriasis.

Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53-Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death

“…More novel was our demonstration that 5FU stimulates tumor-selective increases in PpIX accumulation. Target tissue selectivity is a feature previously reported for other neoadjuvants such as methotrexate (18) and calcitriol in human psoriasis (29) and murine squamous cell carcinomas (24). Enhanced accumulation in tumor cells is important, but even more important may be the fact that 5-FU improves PpIX homogeneously within all cells in the tumor.…”

Combination of Oral Vitamin D3 with Photodynamic Therapy Enhances Tumor Cell Death in a Murine Model of Cutaneous Squamous Cell Carcinoma

“…ALA‐PDT offers the advantage of dual selectivity, because both the PpIX and the visible light can be localized to the tumor, minimizing any damage to the normal tissue. In dermatology clinics, ALA‐PDT is successfully used for treatment of actinic keratosis (sun‐induced precancers) and squamous carcinoma in situ .…”

“…Cancer cells often bypass normal physiological controls on pathways of growth, differentiation and survival to circumvent the cell death and the concept of cPDT is to counteract these abnormalities, using selected small molecule agents. Thus, we found that certain differentiation promoting agents such as methotrexate (MTX) , vitamin D 3 and 5‐fluorouracil (5‐FU) , when given prior to ALA‐PDT, make cancer cells more susceptible to cell killing through accumulation of higher levels of PpIX. We have successfully tested the cPDT concept in various preclinical models including cultured cells , 3D organotypic models in vitro and murine tumor models in vivo , using MTX, vitamin D 3 , or 5‐FU in a 3‐day pretreatment regimen.…”

Photodynamic Therapy and the Biophysics of the Tumor Microenvironment

“…Cells that are poorly differentiated and rapidly proliferating, as is common in many tumors, may produce insufficient amounts of PpIX . One area of investigation to address this issue involves the use of cellular differentiators such as vitamin D or its analogues, methotrexate, retinoic acid, 5‐fluorouracil acid, iron chelators and the androgens 5α‐dihydrotestosterone (DHT) and R1881 .…”