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The origin and meaning of the term “photodynamic” (as used in “photodynamic therapy”, for example)
3. Photo&m.
Photobid.
B: Biol., 9 (1991)
369-374
369
News and Views
The origin and meaning of the term “photodynamic” in “photodynamic therapy”, for example)
(as used
John D. Spikes Department
of Biology,
University
of Utah, Salt Lake City,
VT 84112 (U.S.A.)
“Photodynamic” is one of the most commonly used words in photobiology at present, primarily because of its application in the term “photodynamic therapy” or PDT. In this photochemotherapeutic modality, the patient is given a photosensitizing drug that is somewhat selectively retained in tumors. After an appropriate period, the tumorous area is illuminated, typically with a laser; this can result in the destruction of the tumor with relatively little permanent injury to the surrounding normal tissues [ 1, 21. This type of therapeutic technique was suggested almost a century ago, as will be described below; however, it was not applied to patient treatment in a major organized way until the middle 1970s largely through the efforts of Dougherty and coworkers [l-3]. Thousands of patients worldwide have now been treated with this modality, with very encouraging results for certain types of tumors [ 1, 21. The term, photodynamic therapy, was used in the early 1970s to describe the photosensitized treatment of malignant tumors in rats [ 41. However, as the technique developed, the phrase “photoradiation therapy” or PRT for tumor treatment came into general use [3]. Later, in 1984, workers in the field started using the designation, PDT, and this is used almost universally today. The purpose of this note is to describe the origin and meaning of the word photodynamic. The early history of ideas on the application of photosensitized reactions in therapy will also be summarized. In the winter semester of 1897-1898, a medical student, Oscar Raab, started an investigation of the toxicity of acridine to paramecia; this work was carried out under the direction of Professor Dr. Hermann von Tappeiner, then Director of the Pharmacological Institute of the Ludwig-Maximilians University in Munich. Initially, Raab found that the apparent toxicity of low concentrations of acridine varied significantly from day to day; however, he soon noted that the toxicity depended on the intensity of sunlight in the laboratory. He was then able to show that low concentrations of acridine and some other colored compounds (“dyes”), such as eosin, that had no effect in the dark, sensitized the rapid killing of paramecia in the light. The light exposures used were without effect on the organisms in the absence of the dyes. As mentioned above, Raab initiated his research during the winter semester. In his dissertation [5], he states: “At this time of the year
loll-1344/91/$3.50
0
Elsevier
Sequoia/Printed
in The Netherlands
370
the light fluctuated greatly and it is to this fact that I am largely beholden for the remarkable results I found.. . “. Using a prism monochromator, as well as liquid light filters, Raab showed that only the wavelengths of light absorbed by the sensitizing dyes were effective in killing the paramecia. Raab’s dissertation was published later in 1900 [5]. However, Professor von Tappeiner published first! He authored a short paper describing Raab’s work, that appeared on January 2, 1900 [6]. In this publication, von Tappeiner suggested that the phenomenon observed by Raab might be the cause of the severe skin inflammation found on light-colored sheep and hogs on sunny days if they had been fed buckwheat leaves. Also, in a very prophetic suggestion, von Tappeiner stated (in my free translation): “. . . consumption of certain fluorescent materials (photosensitizers) and the resulting action of light can also have a therapeutic application. . . in areas like dermatology.. . “; he assumed that all photodynamic sensitizers were fluorescent. The study of photosensitized reactions in biology became very popular over the next few years, and it was soon established that many kinds of biological systems (enzymes, viruses, cells, animals, plants) could be sensitized to damage or destruction by light in the presence of any one of a number of different sensitizers [ 71. A more recent summary of the types of biomolecules and organisms sensitive to photodynamic action may be found in ref. 8. It was also soon demonstrated that oxygen was required for the effectiveness of the sensitizers used in these early experiments [ 7, 9 1. von Tappeiner was a leader in the study of photosensitized processes in biology and medicine for a number of years. He and his coworkers published many papers, including a book of collected references from their group [lo]. In 1903, von Tappeiner and Jesionek authored a short paper [ 1 l] that anticipated a number of examples of photochemotherapy. They proposed the use of a photosensitizer, such as eosin, plus light for the treatment of several skin diseases including herpes, molluscum contagiosum, pityriasis versicolor and psoriasis vulgaris; apparently no experiments to test these suggestions were made at the time. However, this paper did include some preliminary clinical data on the eosinsensitized phototherapy of condylomata lata infections of the female genitalia, lupus of the skin and skin cancer. Later, additional studies were reported on the photosensitized treatment of skin cancer in patients using eosin and other dyes, with generally favorable results [ 121. Some early investigators suggested that these reactions were simply sensitized photo-oxidation processes, but this idea did not appeal to the biomedical scientists. In 1904, von Tappeiner and Jodlbauer coined the term “photodynamische Wirkung” (which we translate as “photodynamic action”) for oxygen-requiring photosensitized reactions in biological systems [ 131. This was perhaps done to distinguish the biological phenomena from physical processes, such as the sensitization of photographic plates by dyes, that had been discovered some years earlier (and that did not require the presence of oxygen). According to Blum [7], von Tappeiner, at the time, apparently felt that the photodynamic process might be the basis for photobiological phenomena in general, but this did not turn out to be the case.
371
Bhun, in his seminal book on photodynamic action [7], recommended that the term “photodynamic” be applied only to those photosensitized reactions in biological systems in which oxygen is consumed. He recognized that there could be sensitized photobiological effects that did not involve oxygen (e.g. some of the reactions sensitized by psoralens), but apparently felt that they should not be called photodynamic. Most, but not all, present investigators use the word, photodynamic, in Blum’s sense. There are objections to the term. As Blum states: “The choice of ‘photodynamic action’ is not altogether a happy one, but has the advantage of priority and usage.. . ” [ 71. Actually, von Tappeiner apparently had some reservations about the term that he originated. In the foreword to his book [lo] it is stated: “Whether or not the name . . .is to be used further or dropped must be left to the discretion of my professional colleagues”. Porphyrins, the main sensitizers used at present for the PDT of tumors in patients, do typically require oxygen for their effects, and there is evidence that the damage to tumors observed during PDT is mediated by singlet oxygen [ 1, 21. I have not been able to find any information as to where Oscar Raab came from, and what he did after completing his medical training in Munich. If anyone knows anything about him, I would appreciate hearing from them.
1 T. J. Dougherty, Photosensitizers: therapy and detection of malignant tumors, Photo&em. Photobiol., 45 (1987) 879-889. 2 C. J. Gomer, N. Rucker, A. Ferrario and S. Wong, Properties and applications of photodynamic therapy, Rcuiiat. Res., 120 (1989) 1-18. 3 T. J. Dougherty, J. E. Kaufman, A. Goldfarb, K. S. Weishaupt, D. Boyle and A. MittIeman, Photoradiation therapy for the treatment of malignant tumors, Cancer Z&s., 38 (1978) 2628-2635. 4 I. Diamond, S. Granelh, A. F. McDonagh, S. Nielsen, C. B. Wilson and R. Jaenicke, Photodynamic therapy of maliiant tumors, Luncet, 2 (1972) 1175-1177. 5 0. Raab, Ueber die Wirkung fluorescirender Stoffe auf Infusorien, 2. Bill. (Munich), 39 (1900) 524-546. 6 H. von Tappeiner, Ueber die Wukung fluorescirender Stoffe auf Infusorien nach Versuchen von 0. Raab, Muench. Med. Wochenschr., 47 (1900) 5-7. 7 H. F. Bhun, Photodynamic Action and Diseases Caused by Light, Rhinehold, New York, 1941 (reprinted with an updated appendix, Hafner, New York, 1964). 8 J. D. Spikes, Photosensitization, in K. C. Smith (ed), The Science of PhotobtiZom, Plenum, New York, 2nd edn., 1989, pp. 79-110. 9 A. Jodlbauer and H. von Tappeiner, Ueber die Beteiligung des Sauerstoffes bei der photodynamischen Wukung fluoreszierender Stoffe, Muench. Med. Wochenschr., 52 (1904) 1139-1141. 10 H. von Tappeiner and A. Jodlbauer, Die Sensibilisierende Wirkung Fkwrescierender Substanzen, Vogel, Leipzig, 1907. 11 H. von Tappeiner and A. Jesionek, Therapeutische Versuche mlt fluoreszierenden Stoffen, Muench. Med. Wochenschr., 50 (1903) 2042-2044. 12 A. Jesionek and H. von Tappeiner, Zur Behandlung der Hautcarcinome mit fluorescierenden Stoffen, Arch. Knin. Med., 82 (1905) 72-76. 13 H. von Tappeiner and A. Jodlbauer, Ueber die Wukung der photodynamischen (fluorescierenden) Stoffe auf Protozoen und Enzyme, Arch. Klin. Med., 80 (1904) 427-487.
Photobid.
B: Biol., 9 (1991)
369-374
369
News and Views
The origin and meaning of the term “photodynamic” in “photodynamic therapy”, for example)
(as used
John D. Spikes Department
of Biology,
University
of Utah, Salt Lake City,
VT 84112 (U.S.A.)
“Photodynamic” is one of the most commonly used words in photobiology at present, primarily because of its application in the term “photodynamic therapy” or PDT. In this photochemotherapeutic modality, the patient is given a photosensitizing drug that is somewhat selectively retained in tumors. After an appropriate period, the tumorous area is illuminated, typically with a laser; this can result in the destruction of the tumor with relatively little permanent injury to the surrounding normal tissues [ 1, 21. This type of therapeutic technique was suggested almost a century ago, as will be described below; however, it was not applied to patient treatment in a major organized way until the middle 1970s largely through the efforts of Dougherty and coworkers [l-3]. Thousands of patients worldwide have now been treated with this modality, with very encouraging results for certain types of tumors [ 1, 21. The term, photodynamic therapy, was used in the early 1970s to describe the photosensitized treatment of malignant tumors in rats [ 41. However, as the technique developed, the phrase “photoradiation therapy” or PRT for tumor treatment came into general use [3]. Later, in 1984, workers in the field started using the designation, PDT, and this is used almost universally today. The purpose of this note is to describe the origin and meaning of the word photodynamic. The early history of ideas on the application of photosensitized reactions in therapy will also be summarized. In the winter semester of 1897-1898, a medical student, Oscar Raab, started an investigation of the toxicity of acridine to paramecia; this work was carried out under the direction of Professor Dr. Hermann von Tappeiner, then Director of the Pharmacological Institute of the Ludwig-Maximilians University in Munich. Initially, Raab found that the apparent toxicity of low concentrations of acridine varied significantly from day to day; however, he soon noted that the toxicity depended on the intensity of sunlight in the laboratory. He was then able to show that low concentrations of acridine and some other colored compounds (“dyes”), such as eosin, that had no effect in the dark, sensitized the rapid killing of paramecia in the light. The light exposures used were without effect on the organisms in the absence of the dyes. As mentioned above, Raab initiated his research during the winter semester. In his dissertation [5], he states: “At this time of the year
loll-1344/91/$3.50
0
Elsevier
Sequoia/Printed
in The Netherlands
370
the light fluctuated greatly and it is to this fact that I am largely beholden for the remarkable results I found.. . “. Using a prism monochromator, as well as liquid light filters, Raab showed that only the wavelengths of light absorbed by the sensitizing dyes were effective in killing the paramecia. Raab’s dissertation was published later in 1900 [5]. However, Professor von Tappeiner published first! He authored a short paper describing Raab’s work, that appeared on January 2, 1900 [6]. In this publication, von Tappeiner suggested that the phenomenon observed by Raab might be the cause of the severe skin inflammation found on light-colored sheep and hogs on sunny days if they had been fed buckwheat leaves. Also, in a very prophetic suggestion, von Tappeiner stated (in my free translation): “. . . consumption of certain fluorescent materials (photosensitizers) and the resulting action of light can also have a therapeutic application. . . in areas like dermatology.. . “; he assumed that all photodynamic sensitizers were fluorescent. The study of photosensitized reactions in biology became very popular over the next few years, and it was soon established that many kinds of biological systems (enzymes, viruses, cells, animals, plants) could be sensitized to damage or destruction by light in the presence of any one of a number of different sensitizers [ 71. A more recent summary of the types of biomolecules and organisms sensitive to photodynamic action may be found in ref. 8. It was also soon demonstrated that oxygen was required for the effectiveness of the sensitizers used in these early experiments [ 7, 9 1. von Tappeiner was a leader in the study of photosensitized processes in biology and medicine for a number of years. He and his coworkers published many papers, including a book of collected references from their group [lo]. In 1903, von Tappeiner and Jesionek authored a short paper [ 1 l] that anticipated a number of examples of photochemotherapy. They proposed the use of a photosensitizer, such as eosin, plus light for the treatment of several skin diseases including herpes, molluscum contagiosum, pityriasis versicolor and psoriasis vulgaris; apparently no experiments to test these suggestions were made at the time. However, this paper did include some preliminary clinical data on the eosinsensitized phototherapy of condylomata lata infections of the female genitalia, lupus of the skin and skin cancer. Later, additional studies were reported on the photosensitized treatment of skin cancer in patients using eosin and other dyes, with generally favorable results [ 121. Some early investigators suggested that these reactions were simply sensitized photo-oxidation processes, but this idea did not appeal to the biomedical scientists. In 1904, von Tappeiner and Jodlbauer coined the term “photodynamische Wirkung” (which we translate as “photodynamic action”) for oxygen-requiring photosensitized reactions in biological systems [ 131. This was perhaps done to distinguish the biological phenomena from physical processes, such as the sensitization of photographic plates by dyes, that had been discovered some years earlier (and that did not require the presence of oxygen). According to Blum [7], von Tappeiner, at the time, apparently felt that the photodynamic process might be the basis for photobiological phenomena in general, but this did not turn out to be the case.
371
Bhun, in his seminal book on photodynamic action [7], recommended that the term “photodynamic” be applied only to those photosensitized reactions in biological systems in which oxygen is consumed. He recognized that there could be sensitized photobiological effects that did not involve oxygen (e.g. some of the reactions sensitized by psoralens), but apparently felt that they should not be called photodynamic. Most, but not all, present investigators use the word, photodynamic, in Blum’s sense. There are objections to the term. As Blum states: “The choice of ‘photodynamic action’ is not altogether a happy one, but has the advantage of priority and usage.. . ” [ 71. Actually, von Tappeiner apparently had some reservations about the term that he originated. In the foreword to his book [lo] it is stated: “Whether or not the name . . .is to be used further or dropped must be left to the discretion of my professional colleagues”. Porphyrins, the main sensitizers used at present for the PDT of tumors in patients, do typically require oxygen for their effects, and there is evidence that the damage to tumors observed during PDT is mediated by singlet oxygen [ 1, 21. I have not been able to find any information as to where Oscar Raab came from, and what he did after completing his medical training in Munich. If anyone knows anything about him, I would appreciate hearing from them.
1 T. J. Dougherty, Photosensitizers: therapy and detection of malignant tumors, Photo&em. Photobiol., 45 (1987) 879-889. 2 C. J. Gomer, N. Rucker, A. Ferrario and S. Wong, Properties and applications of photodynamic therapy, Rcuiiat. Res., 120 (1989) 1-18. 3 T. J. Dougherty, J. E. Kaufman, A. Goldfarb, K. S. Weishaupt, D. Boyle and A. MittIeman, Photoradiation therapy for the treatment of malignant tumors, Cancer Z&s., 38 (1978) 2628-2635. 4 I. Diamond, S. Granelh, A. F. McDonagh, S. Nielsen, C. B. Wilson and R. Jaenicke, Photodynamic therapy of maliiant tumors, Luncet, 2 (1972) 1175-1177. 5 0. Raab, Ueber die Wirkung fluorescirender Stoffe auf Infusorien, 2. Bill. (Munich), 39 (1900) 524-546. 6 H. von Tappeiner, Ueber die Wukung fluorescirender Stoffe auf Infusorien nach Versuchen von 0. Raab, Muench. Med. Wochenschr., 47 (1900) 5-7. 7 H. F. Bhun, Photodynamic Action and Diseases Caused by Light, Rhinehold, New York, 1941 (reprinted with an updated appendix, Hafner, New York, 1964). 8 J. D. Spikes, Photosensitization, in K. C. Smith (ed), The Science of PhotobtiZom, Plenum, New York, 2nd edn., 1989, pp. 79-110. 9 A. Jodlbauer and H. von Tappeiner, Ueber die Beteiligung des Sauerstoffes bei der photodynamischen Wukung fluoreszierender Stoffe, Muench. Med. Wochenschr., 52 (1904) 1139-1141. 10 H. von Tappeiner and A. Jodlbauer, Die Sensibilisierende Wirkung Fkwrescierender Substanzen, Vogel, Leipzig, 1907. 11 H. von Tappeiner and A. Jesionek, Therapeutische Versuche mlt fluoreszierenden Stoffen, Muench. Med. Wochenschr., 50 (1903) 2042-2044. 12 A. Jesionek and H. von Tappeiner, Zur Behandlung der Hautcarcinome mit fluorescierenden Stoffen, Arch. Knin. Med., 82 (1905) 72-76. 13 H. von Tappeiner and A. Jodlbauer, Ueber die Wukung der photodynamischen (fluorescierenden) Stoffe auf Protozoen und Enzyme, Arch. Klin. Med., 80 (1904) 427-487.