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Brandishing light and healing the masses. (Articles).

The idea of using ordinary visible light and a harmless drug to treat cancer and other diseases may sound a bit far-fetched, but it is now an established treatment in many hospitals, and it is known as photodynamic therapy.

The scientific process involved in photodynamic therapy is called photosensitization. The process makes use of light to convert a normally non-reactive molecule into a reactive form. From a historical perspective, photosensitization has been used for over 3,000 years. The Egyptians, Chinese and Indians have used photosensitization in attempts to cure such disorders as vitiligo, rickets, psoriasis, skin cancer and psychosis (1, 2). The procedure included the smearing of plant extracts on the skin, followed by an exposure of the skin to the sun's rays.

The scientific understanding of the process involved in photodynamic therapy can be traced to a few key experiments reported at the turn of the last century. In January of 1900, Professor Hermann von Tappeiner published a short report (3) in which he described a discovery made by his student, Oscar Raab. Raab had found that low concentrations of dyes, such as acridine, were able to photo-induce the rapid killing of paramecium. What was important is this: This reaction did not proceed in the absence of light.

At this time, von Tappeiner predicted that certain fluorescent materials, in combination with light, could have beneficial effects in dermatological medicine. Later in this same year, Raab published the details of his experiments (4). Von Tappeiner began to exploit these new findings, and in 1903, in collaboration with the dermatologist A. Jesionek, published clinical data showing attempts to use eosin as a photosensitizer in order to cure skin cancer, lupus of the skin and condylomata lata of the female genitalia (5). At this time von Tappeiner and Jesionek further suggested that eosin could possibly be an effective photosensitizer for the treatment of other skin disorders such as pityiasis vericolor, herpes, mulluscum contagiosum and psosiasis vulgaris.

In 1904, Tappeiner and Jodlbauer (6) reported that the presence of oxygen was a necessary requirement in order to obtain photosensitization by acridine. In order to classify oxygen dependent photosensitization as a special case, Tappeiner introduced the word 'photodynamic' in order to distinguish this new phenomenon from the photosensitization that occurs on photographic plates. Photodynamic action was soon reported to occur in most kinds of biological systems, including plants, animals, cells, viruses, and specifically to biomolecules such as enzymes, toxins and proteins (7).

Photosensitivity due to porphyrins was first reported by Hausmann in 1911 (8). One of the most dramatic demonstrations of porphyrin photosensitization was reported by Meyer-Betz, an Austrian physician, who injected himseli with 200 mg of hematoporphyrin IX. Upon going out in the sunlight, his face swelled up to the extent that his eyes were practically shut. The effect lasted for several months, with a gradual return to normal (9). In 1972, Diamond et al. first reported on the use on hematoporphyrin to treat malignant tumours via photodynamic theapy (10). Much of the driving force for the development of photodynamic therapy certainly comes from the work of Dougherty and co-workers (see, for example, ref. (11)).

The type of molucules that can act as photosensitizers in biological systems is very large. These include naturally occurring molecules such as chiorophylls, porphyrins, phthalocyanines, flavins, thiazine dyes, acridine dyes, anthraquinone dyes, xanthene dyes, hypercin, tetracyclines, sulfanilamides, psoralens, nalidixic acid, coal tar derivatives, chlorpromazines and aminobenzoic acid derivatives, to name but a few.

For a photosensitizer to be successfully used in medicine, it must answer several criteria. First, it must not, by itself, be toxic to the patient. Second, it must be selectively retained in the diseased tissue, and be cleared from all normal tissue in a relatively short time. Third, the photosensitizer must absorb light that can be transmitted through tissue, namely in the red to infrared region of the electromagnetic spectrum. If the above conditions are met, then one can hope to use two individual non-toxic elements, i.e., drug and light, in order to destroy diseased tissue. Molecules that meet the above three basic conditions are often highly conjugated molecules such as porphyrins, chiorins, bacteriochlorins or plithalocyanines. The structure of a naturally occurring porphyrin, Protoporphyrin IX, is shown in Fig. 1.

For photosensitizers to be selectively retained in diseased tissue, they must act similar to dyes that stain different cells or tissues for use in microscopy. The reason why photosensitizers are retained longer in tumours and other diseased tissues is not entirely clear. Increased blood vessel permeability, as well as poor lymphatic drainage in neoplastic tissues, may contribute to the retention of the drug in neoplastic lesions. The lower pH value of interstitial fluid in tumours facilitates the selective biodistribution of photosensitizing dyes, increasing their lipophilic character and uptake into malignant cells [12, 13].

Highly conjugated molecules such a parphyrins have low-lying excited singlet states that can be excited by light in the 600 to 800 nm region, corresponding to the wavelengths that transmit quite deeply into human tissues. For example, 630 nm light penetrates the first 5 mm of most tissues, whereas photons at 700 to 800 nm reach cells as deep as 1 to 2 cm [14, 15]. Once excited, these molecules generally lose about 10% of their excitation energy via fluorescence. This emission can be seen as bright pink/red fluorescence and is a very useful adjunct in detecting lesions.

While the detection of tumours by fluorescent drugs is now routinely used in many hospitals, it is not a new phenomenon. It has long been observed that protoporphyrin IX, or some closely related species has the ability to accumulate and be retained somewhat selectively by malignant tissue and the strong red fluorescence of the retained porphyrin has been used for tumour detection since the 1920s [16-20]. Modern instrumention allows for easy detection of such fluorescence.

The photograph in Fig. 2 shows such fluorescence from protoporphyrin IX present in a human basal cell carcinoma, a type of skin cancer. While such emission easily delineates the surface boundary of skin cancer, the measurement of the tumour depth is a much more complicated problem, which is currently receiving a great deal of study in the hope of developing a diagnostic test known as an optical biopsy [21]. While still in its infancy of development, such a procedure would represent a noninvasive method of detection of diseased tissue. A rapid, non-invasive, optically based biopsy method would represent a significant advantage over conventional biopsies, especially since whole areas could be monitored continuously.

The actual mechanistic process of photodynamic therapy incorporates mechanistic details that involve physics, chemistry and biology. The chemistry and physics roles can best be seen via a Jablonski energy diagram, as shown in Fig. 3. Light is absorbed by the photosensitizer and is thus 'energized' to a higher excited state. Most large molecules have singlet ground states, and excitation leads to excited singlet states. The chemical reactivity that is responsible for cancer killing does not originate from the sensitizer, but rather from another molecule that can capture the excitation energy from the photosensitizer. The molecule believed to do this task in photodynamic therapy is ordinary molecular oxygen. Oxygen is involved in the energy producing process of cells, and is thus found throughout the body. Oxygen is an anomalous molecule in that its ground state is a triplet, i.e., it has two unpaired electrons in its ground state. Oxygen acts as the substrate, picking up the excitation energy from the photose nsitizer triplet excited state, and thus becomes an energized reactive species.

Oxygen is a singlet in its excited reactive state. It is a very powerful oxidizing reagent, with a lifetime of 3 [micro]s in water and about 200 ns in cells. During this short time in cells, it has a mean free path of approximately 45 nm, enabling it to react with many neighbouring molecules. Singlet oxygen has an affinity for double bonds, and it is believed to react primarily with double bonds found in cellular membranes. This chemical reaction is the initial step that is then quickly followed by a series of biochemical changes that can lead to cell death, either via necrosis (cell killing) or via apoptosis (programmed cell death). The overall process of photodynamic therapy is outlined in Fig. 4.

Photosensitizers that are used in photodynamic therapy are often related to 'natural' molecules. For example, the first photodynamic therapy agent (photodynamic therapy agents are referred to as 'photo-chemotherapeutic agents') was actually derived from cow's blood. In order to make it soluble, the natural porphyrin found in cow's blood had to be first extracted and then modified in order to render it soluble. Such 'transformed' porphyrins are no longer natural to the human body and there is a tendency for the body to try and reject them as foreign bodies.

One unique approach to photodynamic therapy is to make use of the body's own natural porphyrin, namely protoporphyrin IX, a component of hemoglobin. An examination of the biosynthetic pathway of protoporphyrin IX reveals a limiting feedback control point that allows one to artificially feed a small amino acid (5-aminolevulinic acid) into the system in order to have the body make excessive amounts of the natural protoporphyrin IX. The body will eventually rid itself of such excessive amounts of the natural photosensitizer, but the transient increase of protoporphyrin IX can be exploited for use in photodynamic therapy (22-25).

The biosynthetic process of converting 5-aminolevulinic acid (ALA) into protoporphyrin IX (PpIX) is part of the overall energy producing system of cells. Since cancer cells are often faster growing, they can be more energy demanding. This may be related to the reason why it is often observed that cancerous cells produce more protoporphyrin IX then their corresponding normal cells. It is possible that the relative amounts of controlling enzymes are different in cancer cells, leading to a differentiation of protoporphyrin IX production rate in cancer cells as compared to normal cells. This observed differentiation forms the basis of what is now known as ALA-PDT (5-aminolevulinic acid induced protoporphyrin IX photodynamic therapy).

Thus, rather than injecting a large, preformed drug that the body either tries to reject or is retained too long in the normal tissues (causing unwanted photosensitivity in normal tissue), ALA-PDT makes use of a small precursor molecule that can be easily administered by different means (topically, orally, via suppositories, infusions, inhalations, or intravenously), leading to the production of a photosensitizing amount of a natural porphyrin in tumours.

The conversion of ALA into PpIX is heavily dependent on regulatory enzymes, in order to maintain the normally required heme concentration. If any of the regulatory enzymes are either lacking or in overabundance, the production of alternative porphyrins (e.g. uroporphyrins or coproporphyrins) or a prolonged overproduction of protoporphyrin IX can lead to diseases known as the porphyrias. For example, in erythropoietic protoporphyria (EPP) there is an excess of protoporphyrin (PP) while in congenital erythropoietic porphyria (Gunther's disease) there are high levels of uroporphyrin (UP), the photosensitivity being more severe in this case (26). Porphyric patients can suffer from light-induced photosensitization, and this fact may well be the basis of the vampire and werewolf legends, since such patients have to be protected from bright light.

For a country with a relatively small population, Canadian scientists/companies have played a surprisingly large role in the development of photodynamic therapy. Although photodynamic therapy was started in the U.S. more than 20 years ago, the current leading PDT company (QLT) is a Canadian company based in Vancouver, BC. The second drug to obtain regulatory approval (ALA) is also a Canadian-based company (DUSA Pharmaceuticals, Inc), with its head office in Toronto, ON. Active research on photodynamic therapy is being carried out in laboratories in Montreal, Sherbrooke, Kingston, Toronto, Calgary, and Vancouver, to name but a few.

Acknowledgement

The expertise of Rebecca Goyan in preparing the figures is sincerely appreciated.

References

(1.) Spikes, J.D., "The Historical Development of Ideas on Application of Photosensitized Reactions in the Health Sciences in Primary Photo-Processes in Biology and Medicine, R.V. Bensasson, G. Jori, E.J. Land and T.G. Truscott, Eds., Plenum Press, New York, NY, pp. 209-227. 1085.

(2.) Harber, L.C., I.E. Kochevar and A.R. Shalita, 'Mechanisms of Photosensitization to Drugs in Humans,' The Science of Photomedicine, J.D. Regan and J.A. Parrish, Eds., Plenum Press, New York, NY, pp. 323-347, 1982.

(3.) H. v. Tappeiner, 'Ueber die Wirkung fluorescierender Stoffe auf infusorien nach Versuchen von O, Raab,' Much. Med. Vochenschr., 47:5, 1900.

(4.) Raab. O., 'Ueber die Wirkung fluorescierender Stoffe auf Infusorien,' Z. Biol., 39:524, 1900.

(5.) Tappeiner, H. v. and A. Jesionek, 'Therapeutische Versuche mit floureszierenden Stoffen,' Munch. Med. Bochenschr., 50:2402, 1903.

(6.) Tappeiner, H. v. and A. Jodlbauer, 'Die sensibilizierende Wirkung fluorescierender Substanzer,' Dusch. Arch. Klin. Med., 80:524, 1904.

(7.) Blum, H.F., 'Photodynamic Action and Diseases Caused by Light,' Reinhold, New York, NY, 1941.

(8.) Hausmann, W. 'The Sensitizing Action of Hematoporphyrin,' Biochemische Zeitschrift, 30:276-316, 1911.

(9.) Meyer-Betz, F. 'Wirkung des Hematoporphyrins und anderer Derivatives des blut und Gallenfarbestoffs,' Dtsch. Arch. Klin. Med. 112;476-503, 1913.

(10.) Diamond, I., A.F. McDonagh, C.B. Wilson, S.L. Granelli, S. Nielsen and R. Jaenicke. 'Photodynamic Therapy of Malignant Tumors,' Lancet, ii:1175-1177, 1972.

(11.) Dougherty, T.J., 'Photosensitizers: Therapy and Detection of Malignant Tumors,' Photochem. Phacobiol. 45:879-889 (1987).

(12.) Bohmer, R.M. and G. Morstyn, 'Uptake of Hematoporphyrin Derivative by Normal and Malignant Cells: Effect of Serum, pH, Temperature and Cell Size.' Cancer Res. 45:5328-5334, 1985.

(13.) Evensen. J.F., 'The Use of Porphyrins and Nonionizing Radiation for Treatment of Cancer,' Acta. Oncol. 8:1103.1110, 1995.

(14.) Driver, I., C.P. Lowdell, and D.V. Ash, 'In Vivo Measurements of the Optical Interaction Coefficients of Human Tumours,' Phys. Med. Biol. 36:805-813, 1991.

(15.) Wilson, B.C., 'The Physics of Photodynamic Therapy,' Phys. Med. Biol. 31:327.360 (1996).

(16.) Policard, A., 'Etude sur les aspects offerts par des tumeurs experimentales examinees a la lumiere de Wood,' C.R. Soc. Biol. 91:1423-1425 (1924).

(17.) Auler, H. and G. Banzer, 'Untersuchungen ueber die Rolle der Porphyrine bei geschwulskranken Menschen und Tieren,' Z. Krebsforsch 53:65-68, 1942.

(18.) Figge, F.H.J., G.S. Weiland and L.O.J. Manganiello, 'Cancer Detection and Therapy: Affinity of Neoplastic Embryonic and Traumatized Tissues for Porphyrins and Metalloporphyrins,' Proc. Soc. Exp. Biol. Med. 68:641-641, 1948.

(19.) Rassmussen-Taxdal, D., G. Ward and F. Figge, 'Fluorescence of Human Lymphatic and Cancer Tissue Following Doses of Intravenous Hematoporphyin,' Cancer 8:78-81, 1955.

(20.) Lipson, R.L., E.J. Baldes and A.M. Olsen, 'The Use of a Derivative of Hematoporphyrin in Tumor Detection,' Journal of the National Cancer Institute, 26:1-8, 1961.

(21.) Stroebele, S., D. Dressler, M.S. Ismail, A. Daskalaki, C. Philipp, H.-P. Berlien, H. Weitzel, M. Liebsch and H. Spielmann, 'Studies on the Optimized Fluorescence Diagnosis of Tumours by Comparing 5-ALA Induced Xenofluorescence and Autofluorescence Intensities of a Murine Tumour-non Tumour Tissue System Cultivated on the CAM,' SPIE, 2627:196-207, 1996.

(22.) Kennedy, J.C., R.H. Pottier and D.C. Pross, 'Photodynamic Therapy with Endogenous Protoporphrin Ix: Basic Principles and Present Clinical Experience,' J. Photochem. Photobiol. B: Biol. 6:143-148, 1990.

(23.) Kennedy, J.C. and R.H. Pottier, 'Endogenous Protoporphyrin Ix, a Clinically Useful Photosensitizer for Photodynamic Therapy,'J. Photochem. Photobiol. B: Biol. 14:275-292, 1992.

(24.) Kennedy, J.C. and R.H. Pottier, 'Using Delta-aminolevulinic Acid in Cancer Therapy, in Porphyric Pesticides : Chemistry, Toxicology, and Pharmaceutical Applications,' S.O. Duke and C.A. Rebeiz, Eds., Amer. Chem. Soc. Symposium Series. No. 559, pp. 291-302, 1994.

(25.) Kennedy, J.C., S.L. Marcus and R.H. Pottier, 'Photodynamic Therapy (Pdt) and 'Photodiagnosis (Pd) Using Endogenous Photosensitization induced by 5-aminolevulinic Acid (Ala): Mechanisms and Clinical Results,' J. Clin. Laser Med. Surg., 14:289-304, 1996.

(26.) G.H. Elder, G.H. Gray and D.C. Nicolson, 'Porphyrias, Review,' Journal of Clinical Pathology, 25:1013-1033 (1972).

Roy Pottier, MCIC, is a professor in the department of chemistry and chemical engineering at the Royal Military College of Canada. His research interests are the application of light activated processes in medicine and chemical defence.
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Title Annotation:photodynamic therapy
Comment:Brandishing light and healing the masses. (Articles).(photodynamic therapy)
Author:Pottier, Roy
Publication:Canadian Chemical News
Geographic Code:1CANA
Date:Oct 1, 2002
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