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A comprehensive overview of photodynamic therapy in the treatment of superficial fungal infections of the skin

https://doi.org/10.1016/j.jphotobiol.2004.06.006Get rights and content

Abstract

Photodynamic therapy (PDT) is a two-step procedure, involving the topical or systemic administration of a photosensitizer followed by selective illumination of the target lesion with visible light, which triggers the oxidative photodamage and subsequent cell death within the target area. In dermatology, PDT has proven to be a useful treatment for a variety of malignant tumors and selected inflammatory diseases. In addition, PDT of several infective viral or bacterial skin diseases has been investigated. These investigations grew out of the positive findings of studies of another important use of PDT: that of disinfection of blood products.

Up to now, little has been published concerning the application of PDT to fungi, probably due to the fact that research funding has been mainly directed towards blood disinfection, and these pathogens show a low risk of transfusion transmission.

However, preliminary findings have demonstrated that dermatophytes and yeasts can be effectively sensitized in vitro by administering photosensitizers belonging to four chemical groups: phenothiazine dyes, porphyrins and phthalocyanines, as well as aminolevulinic acid, which, while not a photosensitizer in itself, is effectively metabolized into protoporphyrin IX. Besides efficacy, PDT has shown other benefits. First, the sensitizers used are highly selective, i.e., fungi were killed at combinations of drug and light doses much lower than that needed for a similar effect on keratinocytes. Second, all investigated photosensitizers lack genotoxic and mutagenic activity. Finally, the hazard of selection of drug resistant fungal strains was never reported.

This paper intends to provide a comprehensive overview of investigative studies about the effects of PDT on yeasts and dermatophytes, and bring attention to this application of PDT which we believe very important in that skin mycosis is so common and PDT is not only cost-effective, but also has the advantages of being highly selective and avoiding the occurrence of drug resistant strains.

Introduction

Photodynamic therapy (PDT) combines the topical or systemic administration of a photosensitizer with the selective illumination of the target lesion with visible light, which results in localized oxidative photodamage and subsequent cell death. This technique is now routinely used in dermatology. The FDA has recently approved 5-aminolevulinic acid (ALA) for the photodynamic treatment of actinic keratosis while the European regulatory authorities have approved methyl-aminolevulinate (MAL) for actinic keratosis and basal cell carcinoma. In addition, PDT with these and other sensitizers has been proven, in worldwide laboratory and clinical studies, to be a promising tool for a wide variety of other skin tumors including squamous cell carcinoma, Bowen’ s disease and cutaneous T-cell lymphoma, and selected inflammatory and infective diseases. This last application grew out of the positive results of research studies concerning photo-induced viral or bacterial inactivation that were conducted with the aim of disinfecting blood products [1], [2]. Up to now these blood disinfection studies pay little or no attention to possible applications of PDT to fungi due to the low risk of transfusion transmission of such pathogens [3].

However, superficial skin mycosis, either caused by Candida species or dermatophytes, is one of the most frequent diseases in human beings and animals and the search for new therapeutic approaches is stimulated by the fact that standard drug treatments are prolonged and expensive and the appearance of drug resistant strains is more and more frequent in high risk groups such as HIV+ patients and cancer patients undergoing chemotherapy [4]. The present paper aims to provide a comprehensive overview of investigative in vitro and in vivo studies of anti-fungal PDT that have been reported so far.

Section snippets

General principles of photosensitization of fungi

Several photosensitizers, mainly belonging to three chemical groups (phenothiazine dyes, porphyrins and phthalocyanines), have been investigated. As a general rule, sensitizers which are medically interesting, are those without dark toxicity, i.e., are devoid of toxicity in the absence of light activation, and, upon irradiation, lack genotoxicity and mutagenicity [5]. The hazard of DNA damages in eukaryotic fungi is furtherly reduced by the presence of a membrane that envelopes the nucleus and

Conclusions and perspectives

Results of experimental investigations have demonstrated that dermatophytes and yeasts can be effectively sensitized in vitro by several dyes belonging to three chemical groups: phenotiazinum, Pp and Pc. In addition, they can effectively metabolize ALA to PpIX. Besides being effective, antifungal PDT is selective because fungi can be killed at dose rates much lower than that which kills keratinocytes. Absence of genotoxic and mutagenic effects on both fungal cells and keratinocytes seems a

Abbreviations

    PDT

    photodynamic therapy

    ALA

    5-aminolevulinic acid

    MAL

    methyl-aminolevulinate

    MB

    methylene blue

    TBO

    toluidine blue

    HpD

    hematoporphyrin derivative

    Pp

    porphyrin

    PpIX

    protoporphyrin IX

    Pc

    phthalocyanine

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