Transcript
Dermatol Clin 25 (2007) 1–4
Introduction to Photodynamic Therapy: Early Experience Michael H. Gold, MDa,b,* a
Gold Skin Care Center, Tennessee Clinical Research Center, 200 Richard Jones Road, Suite 200, Nashville, TN 37215, USA b Vanderbilt University Medical School, Vanderbilt University Nursing School, Nashville, TN 37215, USA
The use of photodynamic therapy (PDT) with appropriate photosensitizers has grown steadily over the past several years, prompting this issue of the Dermatologic Clinics. I am grateful to the publishers for allowing me the opportunity to edit this issue on a field of study that truly is close to my heart. I have been involved in the United States’ study of PDT since its introduction in the late 1990s. I have had the opportunity to study PDT on a variety of dermatologic disorders, including actinic keratoses (AK), photorejuvenation, inflammatory acne vulgaris, sebaceous gland hyperplasia, and hidradenitis suppurativa. I also have been fortunate to collaborate with other investigators from all over the world to learn how they use PDT, how they view the field, and how PDT is working in countries all over the world. The history of PDT can be traced to the early 1900s. Raab [1] first reported, in 1900, that paramecia cells (Paramecium caudatum) were unaffected when exposed to acridine orange or light, but that they died within 2 hours when exposed to both at the same time. Von Tappeiner and Jodblauer [2], in 1904, first described the term
Dr. Gold is a consultant for Dusa Pharmaceuticals, speaks on their behalf, receives honoraria, and performs research on their behalf. Dr. Gold also is a consultant for numerous pharmaceutical and device companies and performs research on their behalf. * Gold Skin Care Center, Tennessee Clinical Research Center, 2000 Richard Jones Road, Suite 220, Nashville, TN 37215. E-mail address:
[email protected]
‘‘photodynamic effect’’ when they showed an oxygen-consuming reaction process in protozoa after aniline dyes were applied with fluorescence. In 1905, Jesionek and Von Tappeiner [3] described experiences with topical 5% eosin. Topical 5% eosin was used as a photosensitizer with artificial light to treat nonmelanoma skin cancers, lupus vulgaris, and condylomata lata in humans successfully. It was postulated that the eosin, in a manner similar to the acridine orange studies, once incorporated into cells, could produce a cytotoxic reaction when exposed to a light source and oxygen. These were the first reports of PDT in patients and led the way to what PDT has become today. After these initial descriptions of eosin and acridine orange use as photosensitizers, researchers turned their attention to the study of porphyrins. In 1911, Hausman [4] reported on the use of hematoporphyrin. He successfully showed that light-activated hematoporphyrin could photosensitize guinea pigs and mice. In 1913, Meyer-Betz [5] injected himself with hematoporphyrin, and noticed that, when the areas he injected were exposed to light, they became swollen and painful. Unfortunately, the phototoxic reaction lasted for 2 months, which created difficulty for its regular use as a photosensitizer. In 1942, Auler and Banzer [6] showed that hematoporphyrin concentrated more in certain dermatologic tumors than in their surrounding tissues; when fluoresced, the tumors were necrotic, which demonstrated the photodynamic response of hematoporphyrin. Figge and his associates [7] later
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reported that hematoporphyrin also was absorbed selectively into other cells, including embryonic, traumatized skin, and neoplastic areas. The principles of PDT in human cancer cells had been established. A proper photosensitizer, in this case hematoporphyrin, could be concentrated in the cancerous cells, and when activated by a proper light source in the presence of oxygen, would be cytotoxic to these cells. In 1978, Dougherty and colleagues [8] presented research with a new photosensitizer, hematoporphyrin purified derivative (HPD). HPD was a complex mixture of porphyrin subunits and by-products. They showed that HPD could be used successfully to treat cutaneous malignancies, with red light being the primary light source. Systemic HPD became the standard for PDT research, and a variety of medical usesdoncologic and nononcologicd emerged for PDT (Box 1). Because of the unique nature of the skin and its accessibility to be studied with natural light or artificial light sources, dermatologic research became a prime focus for PDT study. HPD, however, remained phototoxic in the skin for several months, which makes its practical use in dermatology difficult. In 1990, Kennedy and his group [9] introduced the first topical porphyrin derivative, known as aminolevulinic acid (ALA). This photosensitizing prodrug had the ability to penetrate the stratum corneum of the skin and be absorbed by actinically damaged skin cells, as well as nonmelanoma skin cancer cells and pilosebaceous units. Their group described the PDT reaction of ALA; once incorporated into a particular cell, ALA is converted to its active form, protoporphyrin IX (PpIX). ALA, the natural precursor of PpIX in the heme pathway. ALA is the prodrug photosensitizing agent; PpIX is the photosensitizer. PpIX has been shown to be photoactivated by a variety of lasers and light sources (Fig. 1). The absorption spectrum of PpIX, with peak absorption bands identified in the blue light and red light spectrums, is shown in Fig. 1. Smaller peaks of energy, in between these major absorption bands, also are identified; this has become important and will become apparent as ALA-PDT moves into the twenty-first century [10]. The heme biosynthetic pathway (Fig. 2) is maintained under a close feedback loop apparatus, which does not allow for buildup of heme or its precursors, such as PpIX, in tissues. Exogenous ALA-forming PpIX is cleared from the body much more rapidly than is its predecessor
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Box 1. Uses of photodynamic therapy Medical uses for PDT Malignancies Lung Esophagus Colon Peritoneum Pleura Gastrointestinal tract Brain Eye Skin Nononcologic conditions Atherosclerosis Infectious diseases Rheumatoid arthritis Dermatologic entities that are treated with ALA-PDT Cutaneous T-cell lymphoma Kaposi’s sarcoma Malignant melanoma Keratoacanthoma Extramammary Paget’s disease Acne vulgaris Sebaceous gland hyperplasia Hidradenitis suppurativa Psoriasis vulgaris Verrucae vulgaris Molluscum contagiosum Actinic chelitis Hirsutism Alopecia areata Photorejuvenation/photoaging Adapted from Gold MH, editor. Photodynamic therapy. In: Cutaneous and cosmetic laser surgery. 1st edition. Elsevier; 2006. p. 277–92; with permission.
photosensitizer, HPD. Therefore, the potential for phototoxicity from ALA-induced PpIX, is much reduceddto days instead of several months. Also, ALA penetrates only actinically damaged skin, which increases the specificity of ALA-PDT. ALA-PDT has taken on two separate identities since Kennedy and colleagues’ introduction of topically applied ALA. In the United States, research has centered on 20% 5-ALA (Levulan Kerastick, Dusa Pharmaceuticals, Wilmington, Massachusetts) and
EARLY EXPERIENCE WITH PHOTODYNAMIC THERAPY
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Fig. 1. PpIX absorption spectrum in vivo. IPL, intense pulse light; KTP, potassium titanyl phosphate; PDL, pulse dye laser. (From Nestor MS, Gold MH, Kauvar AN, et al. The use of photodynamic therapy in dermatology: results of a consensus conference. J Drugs Dermatol 2006;5:140–54; with permission.)
Fig. 2. Heme biosynthetic pathway.
its ability to treat AK, photorejuvenation, inflammatory acne vulgaris, sebaceous gland hyperplasia, and hidradenitis predominantly. In Europe, research has centered on the methyl ester of 5-ALA (Metvix, PhotoCure ASA, Oslo, Norway) and its uses in treating nonmelanoma skin cancers and AK. Interest in photorejuvenation and inflammatory acne vulgaris is at its infancy [10]. This issue explores the various drugs, the various indications for each drug, and allows the reader the opportunity to determine if PDT can play a vital role in his/her daily practice of medicine. This issue highlights some of the brightest minds that are involved in the study of PDT from all over the world. PDT is a global subspecialty, and it is important to view it in this manner. PDT has several uses; the primary ones are highlighted by
investigators who share the passion that I have for PDT. As I describe at the end of this issue, all of the indications and uses for PDT are new and exciting; however, the potential role that PDT has as a chemoprevention therapy is huge, and something that I cannot stress to colleagues enough. I hope that you enjoy this issue and I hope that it excites you to enter the world of PDT.
References [1] Raab O. Ueber die wirkung fluoreszierenden stoffe auf infusorien. Z Biol 1900;39:524–6. [2] Von Tappeiner H, Jodblauer A. Uber die wirkung der photodynamischen (fluorescierenden) staffe auf protozoan und enzyme. Dtsch Arch Klin Med 1904;80:427–87.
4 [3] Jesionek A, Von Tappeiner H. Behandlung der hautcarcinome nut fluorescierenden stoffen. Dtsch Arch Klin Med 1905;85:223–7. [4] Hausman W. Die sensibilisierende wirkung des hamatoporphyrins. Biochem Zeit 1911;276–316. [5] Meyer-Betz F. Untersuchungen uber die bioloische (photodynamische) wirkung des hamatoporphyrins und anderer derivative des blut-und gallenfarbstoffs. Dtsch Arch Klin Med 1913;112:476–503. [6] Auler H, Banzer G. Untersuchungen ueber die rolle der porphyrine bei geschwulstkranken menschen und tieren. Z Krebsforsch 1942;53:65–8. [7] Figge FHJ, Weiland GS, Manganiello LDJ. Cancer detection and therapy. Affinity of neoplastic
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embryonic and traumatized tissue for porphyrins and metalloporphyrins. Proc Soc Exp Biol Med 1948;68:640. [8] Dougherty TJ, Kaufman JE, Goldfarb A, et al. Photoradiation therapy for the treatment of malignant tumors. Cancer Res 1978;38:2628–35. [9] Kennedy JC, Pottier RH, Pross DC, et al. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experiences. J Photochem Photobiol B 1990;6:143–8. [10] Gold MH, Goldman MP. 5-Aminolevulinic acid photodynamic therapy: where we have been and where we are going. Dermatol Surg 2004;30: 1077–84.
