Aust. N . Z . J .


Surg. 19!31,61,340-348

A HISTORY OF PHOTODYNAMIC THERAPY M.D.DANIELL AND J. s. HILL Higginbotham Neuroscience Research Institute, Department of Surgery, Royal Melbourne Hospital, Parkville, Victoria

The origins of light as a therapy in medicine and surgery are traced from antiquity to the modem day. Phototherapy began in ancient Greece, Egypt and India but disappeared for many centuries, only being rediscovered by Western civilization at the beginning of the twentieth century through the Dane, Niels Finsen, and the Germans Oscar Raab and Herman von Tappeiner. The discovery of the tumour-localizing ability of haematoporphyrin,together with its phototoxic effect on tumour cells led to the development of photodynamic therapy, a promising tool in modem cancer treatment. Key words: cancer, haematoporphyrin, history, laser, photodynamic therapy, phototherapy, tuberculosis, tumour.

Introduction The use of light as a therapeutic tool in surgery is becoming increasingly important, with the routine use of lasers for photocoagulation and in the photodynamic therapy of cancer. The use of light as a therapy in human diseases has a very long history, stretching back into antiquity. There was a long period in which its uses were not appreciated, however, and only this century, through photodynamic therapy and psoralen molecules and ultraviolet A radiation (PUVA) therapy of some dermatological conditions, has light undergone a renaissance as a useful therapeutic tool in medicine and surgery. The rediscovery and development of phototherapy is also remarkable in that it was not until the second half of the 20th century that the English-speaking world began to appreciate its full potential. It is only by translating the old German, French and Danish texts that the discoveries of these early pioneers can be appreciated. The origins of photodynamic therapy have been investigated by reviewing this early literature that, until now, has been largely neglected. This paper traces the development of light as a treatment and the use of photodynamic therapy in surgery. The interaction of light with some living cells is vital for their survival and yet under certain circumstances can lead to their destruction. Light is necessary for the production of carbn dioxide and oxygen in plants via its interaction with magnesium dihydroporphyrin, better known as chlorophyll, in the Correspondence: Dr M. D. Daniell. Department of Surgery, Royal Melbourne Hospital, Parkville. Vic. 3052, Australia. Accepted for publication 12 December 1990.

photosynthetic process which forms the basis for iife on this planet. Yet there are simultaneous phototoxic reactions, the result of singlet oxygen formation, that would prove rapidly lethal if they were not quenched by the orange and yellow carotene pigments of plants. In humans, naturally occurring porphyrins, usually in iron complexes such as haemoglobin, myoglobin and cytochrome, are also essential for life and are operative in all aerobic cells. However, disturbance of synthesis of porphyrins responsible for the haem group leads to a class of diseases called porphyrias, each with a unique pattern of over-production, accumulation and excretion of intermediaries of haem biosynthesis. The main clinical manifestations are intermittent episodes of nervous system dysfunction and sensitivity of the skin to sunlight. This skin photosensitization is due to porphyrin accumulation and the consequent photodynamic action, after light activation, of singlet oxygen induced tissue damage. Similar phototoxic reactions have been used for the treatment of a variety of diseases including psoriasis, vitiligo and, more recently, cancer, via photodynamic therapy. This technique exploits naturally occurring but usually suppressed reactions. A photosensitizing dye is administered which localizes specifically in the tumour and is subsequently activated by light (usually a laser). When the sensitizer absorbs light of the appropriate wavelength it is converted from a stable electronic structure (ground state) to an excited state (singlet state). The short-lived singlet state may undergo conversion to a long-lived excited state (triplet state), which is the photo-active species responsible for the photochemical generation of cytotoxic products. Interaction of the triplet state with oxygen



produces singlet oxygen, an electronically excited state of oxygen which is highly reactive in biological systems and leads to photo-oxidation and cell death.’ The photosensitizer dyes used are usually porphyrins, flat molecular tablets approximately 7A square with a central hole that can accommodate a metal ion.

History of phototherapy The first uses of light as a therapeutic agent go back many centuries. It was used by the Egyptians, Chinese and Indians in the treatment of many diseases including vitiligo, rickets, psoriasis, skin cancer and even One of the earliest known reports of the sun as a therapeutic agent was heliotherapy, introduced by the Greeks 3000 years ago. The Greeks preferred a form of heliotherapy whereby total body exposure to the sun, or arenation, took place as the participants lay nude in specially set aside areas. Herodotus, the renowned physician of the 2nd century BC was the father of heliotherapy . His teaching stressed the usefulness of exposure to the sun for the restoration of health. Sun worship was the basis of many ancient religions in Europe, Asia and the Americas and this may have had as much to do with the healing prop erties of the sun as with their importance to agriculture. With the advent of Christianity both sun worship and the use of sunlight as a healing modality came to be regarded as pagan practices, although they continued in many forms. It was not until the late 18th century that the beneficial effects of exposure to the sun became reestablished as effective therapy for rickets. A 19th century physician, Cauvin, stated in 1815 that ‘Sunlight is a curative agent for scrofula, rickets, scurvy, rheumatism, paralysis, swellings and dropsy and muscle weakness’.6 Phototherapy was developed into a science and popularized by the Danish physician Niels Finsen who initiated the use of carbon arc phototherapy for lupus vulgaris and won the Nobel prize in 1903 for his w o k 7 Finsen was born in the Faroe Islands and his interest in the contrasts of light and dark in the Arctic Circle led him to study the effects of light on living organisms. Finsen conducted experiments on light and published a paper in 1893on treatment of smallpox with red light, which prevented suppuration of pust u l e ~Later . ~ he found actinic rays to be responsible for the bactericidal property of sunlight, and this enabled him to develop a method of treatment of lupus vulgaris by ultraviolet rays. The Finsen Light Institute was founded in Copenhagen in April 18% and is still an active establishment. Princess Alexandra, wife of the future Edward VII, was responsible for introduction of her countryman’s discovery to England. By the turn of the century she was


encouraging doctors to apply phototherapy at the London Hospital, of which she was president. A plaque at the base of a statue of Queen Alexandra commemorates her contribution (Figs 1, 2). Today phototherapy is most widely used in the treatment of infants with neonatal jaundice, a treatment developed by Cremer er al. at Rochford Hospital in &sex more than 30 years ago (Figs 3-5).7’

Ng. 1. Plaque commemorating Queen Alexandra visiting patients with lupus vulgaris beiig treated with phototherapy. Located on pedestalof statue of Queen Alexandra, London Hospital, London. From New Scientist, 28 January 1989.

History of photochemotherapy Photochemotherapy, or use of an exogenous sensitizer to absorb photons and then react for a therapeutic effect, also has a long history. Psoralens were used in India as early as 1400BC.’ Detailed descriptions in India’s s a d book Atharva-Veda (1400BC) indicate that Hindus practised the ancient Ayurvedic system of medicine using psoralens obtained from the seeds of Psoralea corylifoliu for repigmentation of vitiligenous skin. Around the 12th century AD, the Egyptians obtained psoralens from another plant, Anmi majus, which grows along the south bank of the Nile river, and used them in the treatment of leucoderma. It was many hundreds of years before Kalbrunner isolated the chemical bergapten or 5-methoxypsoralen from bergamot oil in 1834, but even he did not think to apply his lotion in the same way as the earlier civilizations. It was not until 1974 that PUVA was found to be effective in the treatment of psoriasis.’ PUVA involves use of psoralen dyes activated by ultraviolet A radiation - that is. light between 320 and 400nm.Subsequently, the development of an artificial, high intensity source of UV-A radiation made PUVA practical for the treatment of psoriasis and vitili o and, more recently, as a part of immunotherapy.B It was at the beginning of the 20th century that Oscar Raab, a medical student of Professor Herman



Fig. 2. Photodynamic therapy today. Gold vapour laser in operation at the Royal Melbourne Hospital.

Fig. 3. 'Le Chalet', the first Dr Rollier's Clinic (opened in 1903) for treatment of patients suffering from surgical tuberculosis.

Fig. 4. The school in the sun for delicate and predisposed children. 'Les Noisetiers' at Cergnat near Leysin.

von Tappeiner in Munich, first examined photosensitized reactions in a scientific way and introduced the subject to Western medicine. loVon Tappeiner's initial interest was in identifying the process by which quinine was effective in malaria whereas other chemicals, in particular acridine, were more toxic against the protozoan in vitro but were not effective in vivo. Hence, von Tappeiner investigated the properties of acridine (a coal tar derivative), initially demonstrating its potency in vitro with serial dilutions. However, Oscar Raab, who was performing the experiment, came upon an apparent paradox at the lowest limit of concentration. Initially the paramecia all died 60min after acridine at dilutions of 1-2OOOO had been added. In a subsequent experiment they lived for 800-1OOOmin, a markedly different result. The only difference in protocol between the two experiments was a great thunderstorm which occurred during one, causing distinctly different light conditions, and so they began to wonder if it was the light that had caused the difference in their results. Subsequent experiments confirmed that acridine and light increased the toxicity whereas acridine alone, light alone, or acridine exposed to light and then added to paramecium were not toxic. Raab's experiments identified the optical property of fluorescence as that responsible for the in vifrotoxicity and realized that it was not the light itself but some product of the fluorescence that was active.



Fig. 5. Extensive lupus vulgaris. cured after I year of heliotherapy. Photographs from a collection of glass lantern slides held in the Medical History Unit of the University of Melbourne.

Raab’s explanation for the toxic property of fluorescence was incomplete, partly because of the limited understanding of the physical nature of fluorescence at that time. His hypothesis was of a transfer of energy from light to chemical, as is seen in plants following absorption of light by chlorophyll. This paper concluded with a prophecy of the future application of fluorescent material as a therapeutic agent in dermatology. Von Tappeiner took over Raab’s research and, with a dermatologist named Jesionek, published clinical data using eosin as a photosensitizer in the treatment of skin cancer, lupus of the skin and chondylomata of female genitalia.” In 1904 von Tappeiner and Jodlbauer reported that the presence of ox gen was a requirement for photosensitization. Y In 1907 these experimentswere collated into a book in which von Tappeiner coined the term ‘photodynamic therapy’ to describe the phenomenon of oxygen-dependent photosensitization. l4 The term ‘photodynamic therapy’ was used to distinguish these reactions from the phenomenon of photosensitization of photographic plates, which was popular at the time and which was the basis for modem photography. Von Tappeiner is probably the most important early pioneer of photodynamic therapy, clearly predicting the photochemotherapeutic application of photosensitizers as early as 1900. He was also the first to attempt phototherapy


of tumours. Three patients with skin tumours had a 5% solution of eosin typically applied, in some cases supplemented by intra-tumour injection dye. The tumour area was irradiated with light, either sunlight or an arc lamp, for several weeks, with reported improvement. In 1905. the same investigators reported on a further six patients.I5 In most of these patients eosin was used at various concentrations, although the sensitizer was supplemented with fluorescein in one case and sodium dichloroanthracine disulphonate in another, and one patient was treated with Grubler’s magdalene red. Again, favourable results were reported in most cases. The first recorded instance of a photosensitizing drug administered parenterally to humans was that of eosin in 1900. Prime, a French neurologist, began to administer eosin orally for the treatment of epilepsy. He observed that dermatitis occurred on areas of the body exposed to light.16

History of haematoporphyrin The history of porphyrins and their role in medicine is. by contrpt. very brief. Haematoporphyrin was first made by Scherer in I 8 4 I . ” Scherer added concentrated sulfuric acid to dried blood and washed the precipitate free of iron. When the iron-free residue was treated with alcohol it took on a blood red colour, and he was able to show in this way that



iron was not essential for the red colour of blood. Three years later Mulder named this purple-red substance iron-free haematin.” The spectrum of this substance and its remarkable fluorescence were described by Thudichum in 1867 in his re rt to the Medical Officer of the Privy CounciLrHoppeSeyler (1871) was the first to describe the purple substance found in iron-free haematin as haematoporphyrin.” The name porphyrin comes from the Greek ‘porphuros’ meaning reddish purple. Prior to this it was known as ‘cruentin’, being a product extracted by alcohol and sulfuric acid from haemoglobin. which was also known as cruorin. The first studies of the biological properties of haemato rphyrin were by Hausmann (1908) in Vienna.‘He reported destruction of paramecia and red blood cells, and observed in detail symptoms and signs of sensitized mice on exposure to light. Hausmann (191 I ) and Pfeiffer (191 I ) reported sensitization in guinea-pigs and white mice with haematoporphyrin, describing fairly acute, subacute and chronic photosensitivity chan es and some phototoxicity with intense ? First proof that porphyrins could act as photosensitizing agents in humans came when the German Friedrich MeyerBetz (1913) injected himself with 200 mg haematoporphyrin. Within minutes after light exposure he noticed severe pain and swelling confined to the light-exposed areasz4 He remained exquisitely photosensitive for more than 2 months. This reaction was studied more recently by Zalar et a / . ( 1973) in two patients similarly photosensitized with haemat~porphyrin.~’ Meyer-Betz and the German chemist Fischer made several observations on the effect of porphyrin structure on photodynamic activity. In 1912 they found that haematoporphyrin sensitized mice but that mesoporphyrin did not, and Fischer (1925) found uroporphyrin almost as phototoxic as haematoporphyrin.26 Hans Fischer was inspired by and commenced a study of one of Gunther’s original patients, a man named Petry, who had been diagnosed as suffering from congenital haematoporphyria. Between 1915 and 1945 he made monumental contributions to porphyrin chemistry, showing that the naturally occurring porphyrins of excreta - uroporphyrin and coproporphyrin - were of a different structure than haematoporphyrin. He was also the first to suggest abandoning the prefix ‘haemato’. except where specifically required. With the exception of Fischer’s laboratory, most work in porphyrins was halted by the First World War. A student of Fischer. Max Lemberg, emigrated to Australia as a refugee in the late 30s. He later wrote the first book in English on p o r p h ~ r i n s . ~ ~ In the period between the wars there were two significant advances in photodynamic therapy. First, selective localization of porphyrins to

tumours was observed by the Frenchman Policard (1924) in Lyon, who noted the spontaneous fluorescence in experimental tumours exposed to a Woods lamp and correctly attributed this finding to accumulation of porphyrin in the turnour.” The second major finding was by Auler and Banzer in Berlin, who were the first to observe photodynamic action involving haematoporphyrin on t u m o ~ r s In . ~ 1942 ~ they investigated the uptake of haematoporphyrin into tumour, proving conclusively its specific uptake and retention, with higher levels in the tumour than in the normal surrounding tissues. During their investigations they noted that the fluorescing tumours tended to be on the whole more necrotic and so for the first time observed photodynamic action by haematoporphyrin on tumours. They followed up these findings with a series of experiments using animals bearing Jensen’s sarcoma and Flicks-Jobling carcinomas. They injected them with photodyn (haematoporphyrin) and subsequently illuminated the tumours with a strong quartz lamp. Sections of the tumours showed marked necrosis and cystic softening. One animal was left with only a superficial scab after 4 irradiations -the tumour had been completely necrosed. Experiments began on humans with tumours but research was interrupted by the Second World War.29 It was more than 20 years before their experiments were repeated.

Post-war advances The findings of Auler and Banzer did, however, stimulate much work on accumulation and retention of porphyrins. Figge (1948) showed selective retention in vivo and recognized the importance of haematoporph rin as a potential tool for the diagnosis of cancer: Rasmussen-Tiurdal. Ward and Figge (1955) studied haematoporphyrin and confirmed its tumour-localizing ability in a variety of tumours.” However, consistent uptake without large doses was not possible and the associated risks of phototoxicity made haematoporphyrin unsuitable as a diagnostic aid in humans. Schwartz ct a/. (1955) investigated the nature of haematoporphyrin and found it to be a crude, variable mixture of numerous porphyrins, many of which had different properties. With partial purification, the pure haematoporphyrin was the poorest localizer and it was the usually discarded residue that showed the greatest affinity for turnours.32 Schwartz focused his attention on tests of the nonhaematoporphyrin fraction and made new preparations trying to purify this more active component. Among these new porphyrin preparations was a acetic-sulfuric acid porphyrin, which has come to be known as haematoporphyrin derivative (HpD). The discovery of HpD was another example of serendipidity in science. In the process of produc-



ing non-haematoporphyrin fractions, Schwartz used a basic purification system that included extraction into a mixture of ethyl acetate and glacial acetic acid, with subsequent esterification in sulfuric acid. Much to his surprise, the product showed enhanced localization in tumours, despite producing a new compound. Further experiments showed that it was the combination of glacial acetic acid and sulfuric acid, with dissolution in dilute alkali, that led to its improved properties. Although Schwartz had failed to purify the porphyrin fractions, he had produced a far more effective tissue localizing agent (pers. comm.). At this stage, Lipson from the Mayo Clinic was convinced by Schwartz to drop his work on haematoporphyrin and take over investigation of this new derivative (Schwartz, pers. comm.). L i p son, together with Baldes, showed enhanced localization in malignant tissue, with improved photodynamic properties. HpD also had a far more constant composition than haematoporphyrin, although it was far from being a pure substance.33*" This material was used in humans to localize tumours of the bronchus, oesophagus and cervix, with good correlation between fluorescing sites and biopsy-proven Despite the preliminary studies of Auler and Banzer and widespread investigation of the localizing properties of HpD, the use of photodynamic therapy with HpD in humans did not begin until the 1960s. In 1966, Lipson er al. reported the first use of HpD to treat cancer in a patient with a large, ulcerating, recurrent breast carcinoma.38 The patient was treated with multiple HpD injections and local exposure of the tumour to filtered light from a xenon arc lamp. The lesion recurred after several weeks but objective evidence of response was found. Berg and Jungstaad in 1966 and 1967 examined methylene blue, thiopyrinine and anachroquinine2-sulfonate as sensitizers with moderate success, observing significant tumour destruction followed by healing of superficial turn our^.^^*^ Effective destruction of tumour cells in vivo was first shown by Diamond et al. (1972) using haematoporphyrin-sensitized glioma cells implanted subcutaneously in rats and followed by fluorescent lamp expo~ure.~' About the same time Dougherty reported that fluorescein could act in a similar way.42 Two years later, using an argon laser and acridine dye, Thomson et al. effectively treated mouse epithelial t ~ r n o u r s . Dougherty ~~ et al. (1975) were the first to show long-term cures in haematoporphyrin-sensitizedmice and rats bearing a variety of tumours and irradiated with a xenon arc lamp filtered to produce a wavelength greater than 600nm.'"' This was non-toxic to the animals and there was minimal damage to overlying skin. In 1976, Kelly and Snell reported HpD uptake in


malignant and pre-malignant lesions of the bladder and reported the treatment of a single case of bladder carcinoma using HpD and light from a mercury lamp dirscted into the bladder by a glass light guide.45 Following the promise of the in vivo testing and encouragement from anecdotal reports. the first systematic human trials were performed by Dougherty er al. in 1978 on a series of 25 patients, with complete or partial response in 111 of 113 cutaneous or subcutaneous malignant lesions.46 Tumours treated included carcinomas of the breast, colon, prostate, squamous cell, basal cell and endometrium, malignant melanoma, mycosis fungoides, chondrosarcoma and angiosarcomas. HpD was injected intravenously at doses of 2.5 and 5 mgkg and a 5000mW xenon arc lamp with a filter producing 600-700nm light was used 1-7 days after injection. No tumour was found to be unresponsive.46 Since then, numerous studies have reported the use of HpD-mediated photodynamic therapy of a wide variety of tumours, notably bladder, lung, oesophagus, stomach (unpubl. data), skin, gynaecological, head and neck, choroidal melanoma and gli~ma.~'-~? The fmt photodynamic therapy of human glioma using haematoporphyrin derivative and helium neon laser was performed by Pema (1980) and showed no improvement in patient survival but some tumour necrosis.68 Since then, trials run by Laws (1981), Wharen ef af. (1983), McCullough et 01. (1984), Muller and Wilson (1990) and Kaye et al. (1988) have shown significant success using photodynamic therapy, especially at higher light doses, following introduction of the gold vapour l a ~ e r . ~ - ~ O

Present status of pbotoaylrpmic therapy and luture directions Today, more than 2000 patients have been treated by photodynamic therapy in uncontrolled clinical trials. Treatment of endobronchial cancer, superticia1 bladder cancer, head and neck cancer, gynaecological cancer, gastrointestinal cancer, ocular cancer, skin cancer and intracranial cancer using haematoporphyrin derivative or its more purified form, Photofrin 11, has shown encouraging results, with tumour response rates of 50- 100%. Phase II1 clinical trials are currently being undertaken in North America for lung cancer, superficial bladder cancer and oesophageal cancer. Photodynamic therapy is a technique that offers special advantages as an adjuvant therapy of malignant brain tumours as it has been shown to be an effective method of controlling local tumour. The major role of photodynamic therapy will continue to be in more aggressive local control of malignancy without extensive damage to surrounding normal structures. The major reasons for failure



of therapy are inadequate dosimetry of light and/or sensitizer to the tumour; with these factors in mind, a logical progression of research can be predicted. Improvements in light dosimetry, including more efficient delivery to the site of action, better understanding of the optical properties of tissues, especially penetration depth, study of photosensitizer quenching and photobleaching, and the development of direct measurement of light fluorescence distribution during photodynamic therapy will improve clinical results markedly. Many of these areas pose problems in basic physics and engineering which must be solved to realize the full potential of photodynamic therapy. The other major area of research will involve the development of more effective and more specific sensitizers. Haematoporphyrin derivative is a mixture of porphyrins, many of which have been shown to be inactive in vivo. Development of pure sensitizers will allow higher doses of more specific sensitizer to be given without fear of unwanted skin photosensitivity, the major side-effect of photodynamic therapy. It will also dramatically improve our understanding of the mechanism of action, especially with new advances in confocal microscopy. Also, sensitizers are being developed that are activated at wavelengths greater than 630 nm, allowing greater penetration of normal tissues. With better understanding of the photophysics, photochemistry and photobiology of photodynamic therapy we should see marked improvement in the clinical efficacy of this treatment modality. which had its beginning in prehistory, and be able to identify a clear indication for its use in the adjuvant therapy of cancer.

Acknowledgements The authors thank Mr A. Kaye and Prof. G.J. A. Clunie for encouragement and advice in the preparation of this paper, Prof. H. Attwood of the Medical History Unit at Melbourne University for the glass lantern slides and New Scientist magazine for the photograph of the plaque. M.D.D. thanks V. Bettinger, who translated the original German texts. We also acknowledge the assistance of Drs S. K. Schwartz and T. J. Dougherty in providing access to unpublished material.

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A history of photodynamic therapy.

The origins of light as a therapy in medicine and surgery are traced from antiquity to the modern day. Phototherapy began in ancient Greece, Egypt and...
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