Photodiagnosis and Photodynamic Therapy (2004) 1, 3—7
Photodynamic therapy: from the beginning D. Kessel Department of Pharmacology, Wayne State University School of Medicine, 540 E Canfield Street, Detroit, MI 48201, USA
KEYWORDS Photodynamic; Neoplasia; Macular degeneration; Atherosclerosis; Tumor localization
Summary Photodynamic therapy relates to the use of drugs + light for treatment of neoplasia, macular degeneration and atherosclerotic plaque. This field has a long history with recent improvements in drug development and light sources promoting clinical approaches. This summary describes recent progress along with an indication of current lines of research. © 2004 Elsevier B.V. All rights reserved.
Early glimmers Photodynamic therapy (PDT) was initially reported just over 100 years ago when Oscar Raab, working in the laboratory of Hermann von Tapiener in Germany, discovered that illumination of microbial cultures in the presence of acridine and related compounds resulted in cell death. Yon Tapiener and Jesionek (Munich Dermatology Clinic) later used topical eosin and light to treat skin tumors, in 1903. A review article by Spikes [1] summarized this early work. This and related phenomena were periodically re-discovered, but the current era of PDT research was initiated by Lipson and Baldes [2] at the Mayo Clinic who reported in 1960 that neoplastic tissues in surgical patients would fluoresce under ultraviolet light after administration of a porphyrin mixture prepared by Dr. Samuel Schwartz (also at the Mayo Clinic). Schwartz and some of the other earlier workers in the field have published a summary of these early studies [3]. A critical observation was that the impurities in commercial hematoporphyrin (HP) were superior tumor-localizing products. They experimented with several synthetic procedures to form what Schwartz termed hematoporphyrin derivative (HPD).
E-mail address: [email protected] (D. Kessel).
Several other investigators examined the properties of HPD as a tumor localizing and phototherapeutic agent but the clinical utility for tumor eradication was not fully realized until a series of investigations was organized by Dougherty’s group at the Roswell Park Cancer Institute in the early 1970s [4—6]. Dougherty established a procedure for HPD preparation and eventually developed a facility that followed guidelines established by the Food and Drug Administration (FDA) for large-scale preparation. Appropriate light sources were also developed. These gradually progressed from arc lamps to laser/fiber optic systems that could be used to place significant light fluxes in the bladder, lung, oesophagus and other body cavities or solid tumors. Other clinical protocols were developed by Hayata’s group in Japan [7], Forbes in Australia [8], and clinical groups in the UK, China, Norway, France, Germany, Italy, Canada, Russia, and The Netherlands.
PDT-oriented conferences In order to provide an opportunity for investigators to compare notes and to discuss progress, Dougherty organized an international symposium in Buffalo in 1977, closely followed by a meeting organized by the NIH who had by then begun to appreciate the implications of PDT for cancer therapy.
1572-1000/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(04)00003-1
4 The NIH also supported a conference I organized at the Washington Hilton in 1981. We had prepared for 100 participants, and had to move the meeting site to progressively larger rooms as more than 400 people eventually turned up. The proceedings of this meeting have been published [9]. In 1984, Dr. Hayata concluded that the organization of periodic international PDT meetings needed to be codified, and organized the first meeting of the International Photodynamic Association in Tokyo, at the Keio Plaza hotel. This was a major undertaking, with nearly one thousand attendees. Subsequent IPA meetings were held in the US, France, Italy, Australia, England, Canada, and most recently in Japan (2003). The 2005 meeting will occur in Germany; in 2007, China. While these are mainly clinical in nature, there has always been an element of basic science at the IPA conferences. At a Ciba Symposium on PDT in London (1989) there were both invited contributions and discussions. The proceedings of this meeting were published (No. 146 in their Symposium series). There is always a significant PDT presence at meetings of the American and European Societies for Photobiology, the Radiation Research Society and other such groups. In 1989, Tom Dougherty initiated a series of PDT sessions at an annual meeting of the Society for Photo-Optical Instrumentation Engineers (SPIE) in California, and there are now annual SPIE meetings in both San Jose, CA and in Europe. These provide an opportunity for PDT workers to meet with a large engineering contingent.
What is HPD? Schwartz did not provide a description of his process for HPD synthesis until 1992 [3]. He had noticed that highly-purified hematoporphyrin was much less active than crude preparations, and developed a procedure to ‘activate’ HP by treatment with a sulfuric—acetic acid mixture, followed by precipitation of the product upon neutralization. This was later found to result in formation of a series of porphyrin esters containing both –CH=CH2 and –CHOH–CH3 side-chains. This product was then dissolved in dilute base to form an injectable solution. The latter stop turned out to be critical in the formation of an active product although this was not realized at the time. During the early development of PDT, substantial efforts were expended in establishing the nature of ‘HPD’. The proceedings of the 1981 conference show seven reports on aspects of structure identification. Later work revealed that treatment of the porphyrin esters with dilute, base resulted in
D. Kessel formation of a complex series of porphyrin monomers, and dimeric, trimeric, and oligomeric porphyrin esters and ethers. While the esters may form initially, they tend to be unstable and HPD is now believed to consist mainly of porphyrin ethers. Several groups carried out the synthesis of HPD for clinical purposes, notably in Australia, Japan, UK, and Norway. A persistent problem was the variable composition of these products. A considerable portion of the product is composed of porphyrin monomers: hematoporphyrin, hydroxyethyl, vinyl-deuteroporphyhrin and protoporphyrin. These components do not significantly add to efficacy are removed in the purification process that results in the preparation of Photofrin. The latter is enriched in the ‘active’ components, i.e., those that promote tumor localization and photosensitization. While the purification steps have not been revealed in the literature, it is likely that these consist of: (a) treatment of the acetylated porphyrins in dilute base for a sufficiently long time to eliminate unstable intermediates, (b) removal of the low molecular-weight monomers by a process amenable to a large-scale preparation, e.g., by filtration through an appropriate membrane, and (c) lyophilization.
Second-generation photosensitizers Although some investigators had suspected that tumor-localization and photosensitization might be confined to the HPD mixture, synthetic work soon revealed that a variety of porphyrins, chlorins, bacteriochlorins, purpurins, texaphyrins, and related compounds were potent photosensitizing agents. The major adverse reaction to Photofrin or HPD was a persistent photosensitization of the skin, so that a patient had to remain away from bright light for several weeks after therapy. Moreover, the absorbance at 630 nm, a wavelength to which tissues are moderately transparent, is very weak. Many of the newer agents had two highly-desirable properties. The long wavelength absorbance band was shifted from the weak 630 nm absorbance of Photofrin to a much greater absorbance in the vicinity of 660—800 nm. This is important since short-wavelength light is readily scattered by tissues and only weakly penetrates, while near IR light can penetrate tissues for >1 cm. Another important consideration is that the newer agents are readily lost from the circulation and from the skin, so that sequestering patients away from bright light is needed for only a short time after drug administration.
Photodynamic therapy: from the beginning A notable element of the ‘second-generation’ group is the use of 5-aminolevulinic acid (ALA) as a metabolic precursor of the photosensitizer protoporphyrin (PP). Administration of ALA leads to biosynthesis of PP in some tissues including, for unknown reasons, sites of neoplasia. While PP eventually leaks into the circulation, it is sufficiently concentrated initially so that irradiation has a phototoxic effect. ALA-induced PDT is extensively used in the clinic, especially for treatment of skin tumors. Among those who have provided significant insights into ALA treatment are Malik and Djaldetti [10] and Kennedy and Pottier [11]. Malik and Djaldetti provided some of the earliest observations and Malik is currently exploring enzymatic determinants of PP biosynthesis, while Kennedy was a pioneer with respect to the clinical use of ALA in clinical protocols.
Engineering approaches PDT requires a photosensitizer (drug), an activator (light) and a co-factor (oxygen). Lack of, any of these can adversely affect efficacy. Use of HPD and its successors for tumor localization by fluorescence requires only the presence of a photosensitizer and an appropriate visualization procedure. Among the earliest studies on light dosimetry and optical properties of tissues are those by Doiron, Profio, Wilson and coworkers [12—14]. Fluorescence detection of lung tumors was pioneered by Doiron and Profio [15]. Oxygenation parameters were also explored [16]. Techniques for optimizing oxygenation are currently being investigated.
PDT mechanisms and indications Irradiation of tissues containing HPD, Photofrin or other sensitizers leads to the formation of an excited state that can pass off the excess energy by fluorescence. This can markedly aid in tumor localization. Another competing process involves the transfer of this energy to dissolved oxygen in tissues. The oxygen is thereby converted to highly reactive species: singlet molecular oxygen and oxygen radicals, which are highly toxic but rapidly react with any nearby biologic molecule. As a result, the phototoxic effect of PDT is confined to the immediate vicinity of drug localization and does not result in adverse effects on remote tissues. While PDT can result in direct killing of malignant cells, it was soon realized that there were other vital elements of the process. These included the partial or complete shut-down of the tumor
5 vasculature [17] and the promotion of an immune response to the residual tumor after PDT [18]. Vascular effects were also involved in the use of PDT to treat macular degeneration [19]. This is a disorder of the vessels in the retina, leading to appearance of a new vasculature that leads to central loss of vision. Several photodynamic sensitizers can control macular degeneration, and are being used routinely for this purpose. PDT has also shown efficacy in treatment of psoriasis. The coupling of photosensitizing agents to antibodies directed against common tumor antigens is being examined as a means for promoting selective photo-killing. It was difficult to establish clear-cut structure— activity relationships with Photofrin or HPD since these were very complex mixtures. As additional sensitizers were developed, it was possible to demonstrate that many sub-cellular sites could be PDT targets, e.g., mitochondria, the endoplasmic reticulum (ER), lysosomes, the golgi, the plasma membrane. Photodamage to these sites can bring about different biologic processes leading to cell death. In cell culture and in animal models, this often involves a mechanism known as apoptosis, initially described by Oleinick’s group [20]. This can result from photodamage to any of several sub-cellular components including the anti-apoptotic protein Bcl-2 [21]. Vascular shut-down leading to loss of nutrients can also trigger apoptosis.
Tumor localization The rationale for localization of HPD and the second-generation sensitizers at neoplastic loci is not yet clear. Jori et al. demonstrated that the porphyrins contained in HPD show affinity for the lipoproteins in plasma [22], and suggested that up-regulation of low-density lipoprotein (LDL) receptors in neoplastic tissues could play a role. But the chlorin NPe6 binds to high-density lipoprotein (HDL) and proteins, and is also a tumor-localizing sensitizer, so the determinants, of the localization phenomena remain uncertain. A visual inspection of implanted tumors in animals, under ultraviolet irradiation, reveals that the tumor vasculature also becomes fluorescent.
Clinical applications Current clinical research is directed toward use of PDT for treatment of neoplastic disease otherwise difficult to control, including tumors of the skin, brain, head and neck, bladder and anywhere where
6 light can be brought either by surface irradiation or by fiber optics. The sole mention of PDT in the New England Journal Medicine occurred when Prout et al., one of the early pioneers, described results of a clinical trial in China [23]. Initially, laser/fiber optic systems were extensively used. The use of these large, expensive and inefficient systems is gradually being replaced by the smaller and much cheaper diode systems. PDT has also been proposed as a potential means for eradicating atherosclerotic plaque in blood vessels, although this is not yet progressed much beyond animal models. Treatment of macular degeneration appears to be the major current clinical application of PDT at present.
Commercial development Commercial development of PDT was slow to develop. Johnson and Johnson obtained patent rights to HPD but did not bring the technology to the clinic. These rights were later sold to QLT, a group in Vancouver, and more recently to Axcan in Toronto. This now has Food and Drug Administration (FDA) or equivalent approval in the US, Canada, Japan, and in some other countries for treatment of lung, bladder and esophageal tumors. A variety of other companies are now involved in synthesis and production of new photosensitizing agents.
Pioneers in PDT development Naming all of the prominent PDF investigators would be impractical but certain individuals can be cited as having made major contributions to the field. Current work is still being carried out by Dougherty and associates in Buffalo. Prominent among the latter are Barbara Henderson (immunology and vascular effects), Ravi Pandey (synthesis), Allan Oseroff (dermatology) and William Potter (instrumentation). Early clinical experiments were conducted by Dr. Denis Cortese and Dr. Eric Edell (Mayo Clinic), Hayata and Kato (Japan), Jeff Wieman (Kentucky), Merrill Biel (Minneapolis), Andrew Kaye (Melbourne) and Paul Muller (Toronto) among others. The Japanese group carried out extensive studies on PDT in lung tumors, Biel applied the procedure to treatment of head and neck tumor otherwise very difficult to deal with, Kaye and Muller followed up in the initial studies on PDT of brain tumors carried out by Gerald McCullough (Adelaide). Many critical details regarding PDT mechanisms were provided by Johan Moan (Norway),
D. Kessel Giulio Jori (Italy), Stan Brown (Leeds), and C.J. Gomer (Los Angeles). Synthetic programs leading to new sensitizers were conducted by Ray Bonnet (London), David Ward (Australia), Allan Morgan (Kentucky), Jonathan Sessler (Texas), Kevin Smith (Baton Rouge), Johan van Lier (Quebec), Stan Brown (Leeds), and Jonathan Sessler (Texas). Instrumentation (lasers, detection systems) and information on photophysics and optical properties of tissues were developed by Dan Doiron and A.E. Profio (California), Brian Wilson (Toronto), Michael Rodgers (Bowling Green), T.G. Truscott (Keale), Lars Svaasand (Trondhelm) and Tom Foster (Rochester). As can be seen by this partial listing, PDT research is an international project, with data provided from multiple sources. What began as a study of photokilling of microorganisms and as a possible means (from fluorescence emission) of identifying tumor sites has now come to involve research into tumor immunology, mechanisms of cell death and many other phenomena far removed from the initial intent.
Further references A collection of pertinent papers relating to the history of PDT from 1948 was published by SPIE in 1993 [24]. The Ciba Symposium (No. 146) on Photodynamic Therapy is available from the publishers (Wiley, Europe) at the following web-site: http://www.wileyeurope.com/ WileyCDA/WileyTitle/productCd-0471923087.html
References [1] Spikes JD. The historical development of ideas on applications of photosensitizer reactions to the health sciences. In: Bensasson RV, Jori G, Land E, Truscott TG, editors. Primary photoprocess in biology and medicine. New York: Plenum Press; 1985. p. 209—27. [2] Lipson RL, Baldes EJ. Hematoporphyrin derivative: a new aid for endoscopic detection of malignant disease. J Thorac Cardiovasc Surg 1961;42:623—9. [3] Dougherty TJ, Henderson B, Schwartz S, Winkelman JW, Lipson RL. In: Henderson BW, Dougherty TJ, editors. Historical perspective in photodynamic therapy. New York: Maurice Dekker; 1992. p. 1—18. [4] Dougherty TJ, Grindey GB, Fiel R, Weishaupt KR, Boyle DG. Photoradiation therapy II. Cure of animal tumors with hematoporphyrin and light. J Natl Cancer Inst 1975;55:115—21. [5] Dougherty TJ, Lawrence G, Kaufman JH, et al. Photoradiation in the treatment of recurrent breast carcinoma. J Natl Cancer Inst 1979;62:231—7. [6] Dougherty TJ, Kaufrnan JE, Goldfarb A, et al. Photoradiation therapy for the treatment of malignant tumors. Cancer Res 1978;38:2628—35.
Photodynamic therapy: from the beginning [7] Hayata Y, Kato H, Konaka C, et al. Photoradiation therapy with hematoporphyrin derivative in early and stage 1 lung cancer. Chest 1984;86:169—77. [8] Forbes IJ, Cowled PA, Leong AS, et al. Phototherapy of human tumours using haematoporphyrin derivative. Med J Aust 1980;2:489—93. [9] Kessel D, Dougherty TJ, editors. Porphyrin photosensitization. New York: Plenum Press; 1981. [10] Malik Z, Djaldetti M. 5-Amninolevulinic acid stimulation of porphyhrin and hemoglobin synthesis by uninduced friend erythroleukenic cells. Cell Differ 1979;8:223—33. [11] Kennedy JC, Pottier R. Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy. Photochem Photobiol 1992;14:275—92. [12] Profio AE, Doiron DR. Dosimetry considerations in phototherapy. Med Phys 1981;8:190—6. [13] Doiron DR, Svaasand LO, Profio AE. Light dosimetry in tissue: application to photoradiation therapy. Adv Exp Med Biol 1983;160:63—76. [14] Wilson BC, Patterson MS. The physics of photodynamic therapy. Phys Med Biol 1986;31:327—60. [15] Doiron DR, Profio E, Vincent RG, Dougherty TJ. Fluorescence bronchoscopy for detection of lung cancer. Chest 1979;76:27—32. [16] Henderson BW, Fingar VH. Oxygen limitation of direct tumor cell kill during photodynamic treatment of a murine tumor model. Photochem Photobiol 1989;49:299—304.
7 [17] Wieman TJ, Mang TS, Fingar VH, et al. Effect of photodynamic therapy on blood flow in normal and tumor vessels. Surgery 1988;104:512—7. [18] Gollnick SO, Vaughan L, Henderson BW. Generation of effective antitumor vaccines using photodynamic therapy. Cancer Res 2002;62:1604—8. [19] Miller JW, Walsh AW, Kramer M, et al. Photodynamic therapy of experimental choroidal neovascularization using lipoprotein-delivered benzoporphyrin. Arch Ophthalmol 1995;113:810—8. [20] Agarwal ML, Clay ME, Harvey EJ, et al. Photodynamic therapy induced rapid cell death by apoptosis in L5178Y mouse lymphoma cells. Cancer Res 1991;51:5993— 6. [21] Kim HR, Luo Y, Li G, Kessel D. Enhanced apoptotic response to photodynamic therapy after bcl-2 transfection. Cancer Res 1999;59:3429—32. [22] Jori G, Beltramimi M, Reddi E, et al. Evidence for a major role of plasma lipoproteins as hematoporphyrin derivative carriers in vivo. Cancer Lett 1984;24:291— 7. [23] Prout Jr GR, Lin CW, Benson Jr R, et al. Photodynamic therapy with hematoporphyrin derivative in the treatment of superficial transitional-cell carcinoma of the bladder. N Engl J Med 1987;317:1251—5. [24] Kessel D, editor. Milestones in photodynamic therapy. Bellingham, WA: SPIE Optical Engineering Press; 1993.
Photodynamic therapy: from the beginning D. Kessel Department of Pharmacology, Wayne State University School of Medicine, 540 E Canfield Street, Detroit, MI 48201, USA
KEYWORDS Photodynamic; Neoplasia; Macular degeneration; Atherosclerosis; Tumor localization
Summary Photodynamic therapy relates to the use of drugs + light for treatment of neoplasia, macular degeneration and atherosclerotic plaque. This field has a long history with recent improvements in drug development and light sources promoting clinical approaches. This summary describes recent progress along with an indication of current lines of research. © 2004 Elsevier B.V. All rights reserved.
Early glimmers Photodynamic therapy (PDT) was initially reported just over 100 years ago when Oscar Raab, working in the laboratory of Hermann von Tapiener in Germany, discovered that illumination of microbial cultures in the presence of acridine and related compounds resulted in cell death. Yon Tapiener and Jesionek (Munich Dermatology Clinic) later used topical eosin and light to treat skin tumors, in 1903. A review article by Spikes [1] summarized this early work. This and related phenomena were periodically re-discovered, but the current era of PDT research was initiated by Lipson and Baldes [2] at the Mayo Clinic who reported in 1960 that neoplastic tissues in surgical patients would fluoresce under ultraviolet light after administration of a porphyrin mixture prepared by Dr. Samuel Schwartz (also at the Mayo Clinic). Schwartz and some of the other earlier workers in the field have published a summary of these early studies [3]. A critical observation was that the impurities in commercial hematoporphyrin (HP) were superior tumor-localizing products. They experimented with several synthetic procedures to form what Schwartz termed hematoporphyrin derivative (HPD).
E-mail address: [email protected] (D. Kessel).
Several other investigators examined the properties of HPD as a tumor localizing and phototherapeutic agent but the clinical utility for tumor eradication was not fully realized until a series of investigations was organized by Dougherty’s group at the Roswell Park Cancer Institute in the early 1970s [4—6]. Dougherty established a procedure for HPD preparation and eventually developed a facility that followed guidelines established by the Food and Drug Administration (FDA) for large-scale preparation. Appropriate light sources were also developed. These gradually progressed from arc lamps to laser/fiber optic systems that could be used to place significant light fluxes in the bladder, lung, oesophagus and other body cavities or solid tumors. Other clinical protocols were developed by Hayata’s group in Japan [7], Forbes in Australia [8], and clinical groups in the UK, China, Norway, France, Germany, Italy, Canada, Russia, and The Netherlands.
PDT-oriented conferences In order to provide an opportunity for investigators to compare notes and to discuss progress, Dougherty organized an international symposium in Buffalo in 1977, closely followed by a meeting organized by the NIH who had by then begun to appreciate the implications of PDT for cancer therapy.
1572-1000/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(04)00003-1
4 The NIH also supported a conference I organized at the Washington Hilton in 1981. We had prepared for 100 participants, and had to move the meeting site to progressively larger rooms as more than 400 people eventually turned up. The proceedings of this meeting have been published [9]. In 1984, Dr. Hayata concluded that the organization of periodic international PDT meetings needed to be codified, and organized the first meeting of the International Photodynamic Association in Tokyo, at the Keio Plaza hotel. This was a major undertaking, with nearly one thousand attendees. Subsequent IPA meetings were held in the US, France, Italy, Australia, England, Canada, and most recently in Japan (2003). The 2005 meeting will occur in Germany; in 2007, China. While these are mainly clinical in nature, there has always been an element of basic science at the IPA conferences. At a Ciba Symposium on PDT in London (1989) there were both invited contributions and discussions. The proceedings of this meeting were published (No. 146 in their Symposium series). There is always a significant PDT presence at meetings of the American and European Societies for Photobiology, the Radiation Research Society and other such groups. In 1989, Tom Dougherty initiated a series of PDT sessions at an annual meeting of the Society for Photo-Optical Instrumentation Engineers (SPIE) in California, and there are now annual SPIE meetings in both San Jose, CA and in Europe. These provide an opportunity for PDT workers to meet with a large engineering contingent.
What is HPD? Schwartz did not provide a description of his process for HPD synthesis until 1992 [3]. He had noticed that highly-purified hematoporphyrin was much less active than crude preparations, and developed a procedure to ‘activate’ HP by treatment with a sulfuric—acetic acid mixture, followed by precipitation of the product upon neutralization. This was later found to result in formation of a series of porphyrin esters containing both –CH=CH2 and –CHOH–CH3 side-chains. This product was then dissolved in dilute base to form an injectable solution. The latter stop turned out to be critical in the formation of an active product although this was not realized at the time. During the early development of PDT, substantial efforts were expended in establishing the nature of ‘HPD’. The proceedings of the 1981 conference show seven reports on aspects of structure identification. Later work revealed that treatment of the porphyrin esters with dilute, base resulted in
D. Kessel formation of a complex series of porphyrin monomers, and dimeric, trimeric, and oligomeric porphyrin esters and ethers. While the esters may form initially, they tend to be unstable and HPD is now believed to consist mainly of porphyrin ethers. Several groups carried out the synthesis of HPD for clinical purposes, notably in Australia, Japan, UK, and Norway. A persistent problem was the variable composition of these products. A considerable portion of the product is composed of porphyrin monomers: hematoporphyrin, hydroxyethyl, vinyl-deuteroporphyhrin and protoporphyrin. These components do not significantly add to efficacy are removed in the purification process that results in the preparation of Photofrin. The latter is enriched in the ‘active’ components, i.e., those that promote tumor localization and photosensitization. While the purification steps have not been revealed in the literature, it is likely that these consist of: (a) treatment of the acetylated porphyrins in dilute base for a sufficiently long time to eliminate unstable intermediates, (b) removal of the low molecular-weight monomers by a process amenable to a large-scale preparation, e.g., by filtration through an appropriate membrane, and (c) lyophilization.
Second-generation photosensitizers Although some investigators had suspected that tumor-localization and photosensitization might be confined to the HPD mixture, synthetic work soon revealed that a variety of porphyrins, chlorins, bacteriochlorins, purpurins, texaphyrins, and related compounds were potent photosensitizing agents. The major adverse reaction to Photofrin or HPD was a persistent photosensitization of the skin, so that a patient had to remain away from bright light for several weeks after therapy. Moreover, the absorbance at 630 nm, a wavelength to which tissues are moderately transparent, is very weak. Many of the newer agents had two highly-desirable properties. The long wavelength absorbance band was shifted from the weak 630 nm absorbance of Photofrin to a much greater absorbance in the vicinity of 660—800 nm. This is important since short-wavelength light is readily scattered by tissues and only weakly penetrates, while near IR light can penetrate tissues for >1 cm. Another important consideration is that the newer agents are readily lost from the circulation and from the skin, so that sequestering patients away from bright light is needed for only a short time after drug administration.
Photodynamic therapy: from the beginning A notable element of the ‘second-generation’ group is the use of 5-aminolevulinic acid (ALA) as a metabolic precursor of the photosensitizer protoporphyrin (PP). Administration of ALA leads to biosynthesis of PP in some tissues including, for unknown reasons, sites of neoplasia. While PP eventually leaks into the circulation, it is sufficiently concentrated initially so that irradiation has a phototoxic effect. ALA-induced PDT is extensively used in the clinic, especially for treatment of skin tumors. Among those who have provided significant insights into ALA treatment are Malik and Djaldetti [10] and Kennedy and Pottier [11]. Malik and Djaldetti provided some of the earliest observations and Malik is currently exploring enzymatic determinants of PP biosynthesis, while Kennedy was a pioneer with respect to the clinical use of ALA in clinical protocols.
Engineering approaches PDT requires a photosensitizer (drug), an activator (light) and a co-factor (oxygen). Lack of, any of these can adversely affect efficacy. Use of HPD and its successors for tumor localization by fluorescence requires only the presence of a photosensitizer and an appropriate visualization procedure. Among the earliest studies on light dosimetry and optical properties of tissues are those by Doiron, Profio, Wilson and coworkers [12—14]. Fluorescence detection of lung tumors was pioneered by Doiron and Profio [15]. Oxygenation parameters were also explored [16]. Techniques for optimizing oxygenation are currently being investigated.
PDT mechanisms and indications Irradiation of tissues containing HPD, Photofrin or other sensitizers leads to the formation of an excited state that can pass off the excess energy by fluorescence. This can markedly aid in tumor localization. Another competing process involves the transfer of this energy to dissolved oxygen in tissues. The oxygen is thereby converted to highly reactive species: singlet molecular oxygen and oxygen radicals, which are highly toxic but rapidly react with any nearby biologic molecule. As a result, the phototoxic effect of PDT is confined to the immediate vicinity of drug localization and does not result in adverse effects on remote tissues. While PDT can result in direct killing of malignant cells, it was soon realized that there were other vital elements of the process. These included the partial or complete shut-down of the tumor
5 vasculature [17] and the promotion of an immune response to the residual tumor after PDT [18]. Vascular effects were also involved in the use of PDT to treat macular degeneration [19]. This is a disorder of the vessels in the retina, leading to appearance of a new vasculature that leads to central loss of vision. Several photodynamic sensitizers can control macular degeneration, and are being used routinely for this purpose. PDT has also shown efficacy in treatment of psoriasis. The coupling of photosensitizing agents to antibodies directed against common tumor antigens is being examined as a means for promoting selective photo-killing. It was difficult to establish clear-cut structure— activity relationships with Photofrin or HPD since these were very complex mixtures. As additional sensitizers were developed, it was possible to demonstrate that many sub-cellular sites could be PDT targets, e.g., mitochondria, the endoplasmic reticulum (ER), lysosomes, the golgi, the plasma membrane. Photodamage to these sites can bring about different biologic processes leading to cell death. In cell culture and in animal models, this often involves a mechanism known as apoptosis, initially described by Oleinick’s group [20]. This can result from photodamage to any of several sub-cellular components including the anti-apoptotic protein Bcl-2 [21]. Vascular shut-down leading to loss of nutrients can also trigger apoptosis.
Tumor localization The rationale for localization of HPD and the second-generation sensitizers at neoplastic loci is not yet clear. Jori et al. demonstrated that the porphyrins contained in HPD show affinity for the lipoproteins in plasma [22], and suggested that up-regulation of low-density lipoprotein (LDL) receptors in neoplastic tissues could play a role. But the chlorin NPe6 binds to high-density lipoprotein (HDL) and proteins, and is also a tumor-localizing sensitizer, so the determinants, of the localization phenomena remain uncertain. A visual inspection of implanted tumors in animals, under ultraviolet irradiation, reveals that the tumor vasculature also becomes fluorescent.
Clinical applications Current clinical research is directed toward use of PDT for treatment of neoplastic disease otherwise difficult to control, including tumors of the skin, brain, head and neck, bladder and anywhere where
6 light can be brought either by surface irradiation or by fiber optics. The sole mention of PDT in the New England Journal Medicine occurred when Prout et al., one of the early pioneers, described results of a clinical trial in China [23]. Initially, laser/fiber optic systems were extensively used. The use of these large, expensive and inefficient systems is gradually being replaced by the smaller and much cheaper diode systems. PDT has also been proposed as a potential means for eradicating atherosclerotic plaque in blood vessels, although this is not yet progressed much beyond animal models. Treatment of macular degeneration appears to be the major current clinical application of PDT at present.
Commercial development Commercial development of PDT was slow to develop. Johnson and Johnson obtained patent rights to HPD but did not bring the technology to the clinic. These rights were later sold to QLT, a group in Vancouver, and more recently to Axcan in Toronto. This now has Food and Drug Administration (FDA) or equivalent approval in the US, Canada, Japan, and in some other countries for treatment of lung, bladder and esophageal tumors. A variety of other companies are now involved in synthesis and production of new photosensitizing agents.
Pioneers in PDT development Naming all of the prominent PDF investigators would be impractical but certain individuals can be cited as having made major contributions to the field. Current work is still being carried out by Dougherty and associates in Buffalo. Prominent among the latter are Barbara Henderson (immunology and vascular effects), Ravi Pandey (synthesis), Allan Oseroff (dermatology) and William Potter (instrumentation). Early clinical experiments were conducted by Dr. Denis Cortese and Dr. Eric Edell (Mayo Clinic), Hayata and Kato (Japan), Jeff Wieman (Kentucky), Merrill Biel (Minneapolis), Andrew Kaye (Melbourne) and Paul Muller (Toronto) among others. The Japanese group carried out extensive studies on PDT in lung tumors, Biel applied the procedure to treatment of head and neck tumor otherwise very difficult to deal with, Kaye and Muller followed up in the initial studies on PDT of brain tumors carried out by Gerald McCullough (Adelaide). Many critical details regarding PDT mechanisms were provided by Johan Moan (Norway),
D. Kessel Giulio Jori (Italy), Stan Brown (Leeds), and C.J. Gomer (Los Angeles). Synthetic programs leading to new sensitizers were conducted by Ray Bonnet (London), David Ward (Australia), Allan Morgan (Kentucky), Jonathan Sessler (Texas), Kevin Smith (Baton Rouge), Johan van Lier (Quebec), Stan Brown (Leeds), and Jonathan Sessler (Texas). Instrumentation (lasers, detection systems) and information on photophysics and optical properties of tissues were developed by Dan Doiron and A.E. Profio (California), Brian Wilson (Toronto), Michael Rodgers (Bowling Green), T.G. Truscott (Keale), Lars Svaasand (Trondhelm) and Tom Foster (Rochester). As can be seen by this partial listing, PDT research is an international project, with data provided from multiple sources. What began as a study of photokilling of microorganisms and as a possible means (from fluorescence emission) of identifying tumor sites has now come to involve research into tumor immunology, mechanisms of cell death and many other phenomena far removed from the initial intent.
Further references A collection of pertinent papers relating to the history of PDT from 1948 was published by SPIE in 1993 [24]. The Ciba Symposium (No. 146) on Photodynamic Therapy is available from the publishers (Wiley, Europe) at the following web-site: http://www.wileyeurope.com/ WileyCDA/WileyTitle/productCd-0471923087.html
References [1] Spikes JD. The historical development of ideas on applications of photosensitizer reactions to the health sciences. In: Bensasson RV, Jori G, Land E, Truscott TG, editors. Primary photoprocess in biology and medicine. New York: Plenum Press; 1985. p. 209—27. [2] Lipson RL, Baldes EJ. Hematoporphyrin derivative: a new aid for endoscopic detection of malignant disease. J Thorac Cardiovasc Surg 1961;42:623—9. [3] Dougherty TJ, Henderson B, Schwartz S, Winkelman JW, Lipson RL. In: Henderson BW, Dougherty TJ, editors. Historical perspective in photodynamic therapy. New York: Maurice Dekker; 1992. p. 1—18. [4] Dougherty TJ, Grindey GB, Fiel R, Weishaupt KR, Boyle DG. Photoradiation therapy II. Cure of animal tumors with hematoporphyrin and light. J Natl Cancer Inst 1975;55:115—21. [5] Dougherty TJ, Lawrence G, Kaufman JH, et al. Photoradiation in the treatment of recurrent breast carcinoma. J Natl Cancer Inst 1979;62:231—7. [6] Dougherty TJ, Kaufrnan JE, Goldfarb A, et al. Photoradiation therapy for the treatment of malignant tumors. Cancer Res 1978;38:2628—35.
Photodynamic therapy: from the beginning [7] Hayata Y, Kato H, Konaka C, et al. Photoradiation therapy with hematoporphyrin derivative in early and stage 1 lung cancer. Chest 1984;86:169—77. [8] Forbes IJ, Cowled PA, Leong AS, et al. Phototherapy of human tumours using haematoporphyrin derivative. Med J Aust 1980;2:489—93. [9] Kessel D, Dougherty TJ, editors. Porphyrin photosensitization. New York: Plenum Press; 1981. [10] Malik Z, Djaldetti M. 5-Amninolevulinic acid stimulation of porphyhrin and hemoglobin synthesis by uninduced friend erythroleukenic cells. Cell Differ 1979;8:223—33. [11] Kennedy JC, Pottier R. Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy. Photochem Photobiol 1992;14:275—92. [12] Profio AE, Doiron DR. Dosimetry considerations in phototherapy. Med Phys 1981;8:190—6. [13] Doiron DR, Svaasand LO, Profio AE. Light dosimetry in tissue: application to photoradiation therapy. Adv Exp Med Biol 1983;160:63—76. [14] Wilson BC, Patterson MS. The physics of photodynamic therapy. Phys Med Biol 1986;31:327—60. [15] Doiron DR, Profio E, Vincent RG, Dougherty TJ. Fluorescence bronchoscopy for detection of lung cancer. Chest 1979;76:27—32. [16] Henderson BW, Fingar VH. Oxygen limitation of direct tumor cell kill during photodynamic treatment of a murine tumor model. Photochem Photobiol 1989;49:299—304.
7 [17] Wieman TJ, Mang TS, Fingar VH, et al. Effect of photodynamic therapy on blood flow in normal and tumor vessels. Surgery 1988;104:512—7. [18] Gollnick SO, Vaughan L, Henderson BW. Generation of effective antitumor vaccines using photodynamic therapy. Cancer Res 2002;62:1604—8. [19] Miller JW, Walsh AW, Kramer M, et al. Photodynamic therapy of experimental choroidal neovascularization using lipoprotein-delivered benzoporphyrin. Arch Ophthalmol 1995;113:810—8. [20] Agarwal ML, Clay ME, Harvey EJ, et al. Photodynamic therapy induced rapid cell death by apoptosis in L5178Y mouse lymphoma cells. Cancer Res 1991;51:5993— 6. [21] Kim HR, Luo Y, Li G, Kessel D. Enhanced apoptotic response to photodynamic therapy after bcl-2 transfection. Cancer Res 1999;59:3429—32. [22] Jori G, Beltramimi M, Reddi E, et al. Evidence for a major role of plasma lipoproteins as hematoporphyrin derivative carriers in vivo. Cancer Lett 1984;24:291— 7. [23] Prout Jr GR, Lin CW, Benson Jr R, et al. Photodynamic therapy with hematoporphyrin derivative in the treatment of superficial transitional-cell carcinoma of the bladder. N Engl J Med 1987;317:1251—5. [24] Kessel D, editor. Milestones in photodynamic therapy. Bellingham, WA: SPIE Optical Engineering Press; 1993.
