3. Modern Aspects of Photodynamic Therapy Application in
Treatment of Oncological Diseases
Photodynamic therapy (PDT) uses the local activation of a photosensitizer accumulated in a tumor by means of light. In the presence of tissue oxygen, this activation brings about a photochemical reaction that destroys tumor cells . The PDT mechanism can be described as follows. When a photosensitizer molecule absorbs a quantum of light, it goes to an excited triplet state. The excited molecule can undergo photochemical reactions of two types. In the first type, the molecule reacts directly with biological molecules. This leads to the generation of free radicals. In the second type, an excited photosensitizer molecule reacts with an oxygen molecule. As a result, singlet oxygen is produced. This substance is a strong oxidant, which is cytotoxic in action. Soon after its development, the photodynamic effect was used in oncology. It proved to be beneficial in the treatment of cancer.
Presently, thousands of scientists and clinical practitioners are studying different aspects of PDT and PDT-related fluorescent diagnosis. By now, PDT has been applied to tens of thousands of cancer patients. At the beginning of 2003 the “Magic Ray” Moscow Center of Laser Medicine was founded in Russia. The main tasks of this Center are as follows:
- PDT treatment of cancer diseases: eye oncological diseases (melanoma); oncological diseases of eye appendix section: eyelids, tear organs, conjuctives; oncological diseases of skin and human body; breast cancer (the first, second and third stage); oncology of bronchi-pulmonary system. At the nearest future we'll be ready to accept the patients with the following localizations of a cancer: abdominal tumors; cancer of a pancreas; gynecology tumors; proctology tumors;
- development of photosensitizers, equipment, and methods for an early diagnosis of endoecological intoxications and precancerous conditions, as well as preventive and therapeutic techniques for precancerous and malignant diseases using photodynamic therapy and antioxidant therapy;
- development and medical application of an international economic cooperation model in the area of photodynamic therapy on the basis of an information net; provision of clinics, medical centers, and individual physicians with commercial equipment, photosensitizers, and therapeutic techniques.
Over the past ten years, much interest has been shown to tetrapyrrol compounds (such as chlorophyll derivatives) . These substances were tested as photosensitizers in the PDT of malignant tumors. The main problem was to increase the selectivity of photosensitizer accumulation in tumors. Poor selectivity resulted in poor therapeutic efficiency. It also brought about hypersensitivity of the patient’s skin to daylight.
Tetrapyrrol structural and functional features made it possible to synthesize compounds with specified properties. As a result, new PDT photosensitizers were built and produced. Such photosensitizers showed higher tumor tropism and higher cytotoxicity to tumor cells. Having analyzed much experimental and clinical data, researchers specified main requirements to an optimum photosensitizer. These requirements included photophysical, chemical-engineering, as well as biological (such as toxic and pharmacokinetic) criteria. Some of the criteria are as follows:
- low toxicity at therapeutic doses in darkness;
- high tumor-targeting accumulation;
- fast elimination from the skin and epithelium;
- absorption peaks in the low-loss transmission window of biological tissues (the far-red and near-infrared bands);
- optimum ratio of the fluorescence quantum yield to the interconversion quantum yield (the former parameter determines the photosensitizer diagnostic capabilities, it plays a key role in monitoring the photosensitizer accumulation in tissues and its elimination from them; the latter parameter determines the photosensitizer ability to generate singlet oxygen);
- high quantum yield of singlet oxygen production in-vivo;
- available manufacturing and synthesis;
- homogeneous composition;
- high solubility in water, injection solutions, and blood substitutes;
- storage and application light stability.
Such photosensitizers are actively sought among chlorin, bacteriochlorin, purpurin, benzoporphyrin, texaphyrin, etiopurpurin, naphthalocyanine, and phthalocyanine derivatives. Special interest is shown to photosensitizers that can be both rapidly accumulated and decomposed. One day, a bank of tumor-targeting photosensitizers will be created (as it has been done for tumor chemotherapy). Such tumor-targeting photosensitizers will be effective for specific nosological and histological forms of cancer .
The “Magic Ray” Moscow Center of Laser Medicine carried out comprehensive investigations of tetrapyrrol chlorin-type macrocycles (chlorophyll-A derivatives). It has to establish the structural and functional features of their accumulation in tumors. It also needed to increase PDT efficiency and to create chlorin-type drugs. At that time, scientists developed a technique for extracting biologically active chlorins from plants. Plant chlorins were found to mainly contain chlorin e6.
Chlorin-type tetrapyrrol photosensitizers were put to biological tests. It was found that they absorb eagerly in the far-red and near-infrared bands. They were also found to have an optimum ratio of quantum yields of fluorescence to interconversion. The phototoxicity of these photosensitizers was greater by an order of magnitude than that of many other photosensitizers. These compounds were inactive in darkness. In general, chlorin-type photosensitizers produced a better toxic effect, as compared to both porphyrin oligomeric and sulfonated phthalocyanine compounds. Furthermore, the body eliminated water-soluble chlorin-type compounds much faster. An organism eliminates chlorin-type photosensitizers within from 1 till 2 days.
Chlorin-type photosensitizers  produced radical changes in the PDT of malignant tumors. The application of Photofrin II relies on a long-term treatment under inpatient conditions, whereas the application of chlorin-type photosensitizers avoids this stage. Instead, the patient receives a one-day or outpatient treatment. A tumor should be irradiated 2 hours after the photosensitizer injection.
In conclusion, we shall dwell on the advantages of and prospects for PDT of cancer. To begin with, we shall estimate the prevalence of this pathology and the economic damage caused by malignant tumors.
Everybody on Earth feels the negative psychogenic effect of cancer. According to the World Health Organization, in 2001, cancer was first diagnosed in 10 million people, and more than 6 million people died of cancer. Most often, cancer strikes the lung and gastrointestinal tract (stomach cancer, esophagus cancer, colon cancer, and rectum cancer). Lung and gastrointestinal cancer constitutes 47 percent of ten most frequent cancer localizations. They also account for 42 percent of cancer-provoked deaths around the world.
Cancer causes a substantial damage to economy. According to the National Institute of Health, the economic damage of cancer in 2001 reached $180.2 billion in the USA alone.
By way of example, consider the economic efficiency of PDT in the treatment of the most frequent forms of cancer. Let us consider accessible tumors. As is known, PDT is most efficient at early stages. Lung and gastrointestinal cancer can rarely be diagnosed at early stages. As a result, despite all of its merits, PDT contributes little to the economy in these cases. The situation changes drastically in the case of skin cancer.
Photodynamic therapy, both in Russia and abroad, is applied in 65 to 70 percent of patients with skin cancer. In this case, PDT yields a 100-percent therapeutic efficiency .
Photodynamic therapy of skin cancer normally requires a single session under outpatient conditions, whereas a routine close-focus X-ray therapy lasts for 2 to 3 weeks. In this sense, PDT provides a much better economic efficiency.
Photodynamic therapy has a similar effect in the case of other superficial malignant tumors. For example, it goes for recurrences and intradermal metastases of breast cancer, primary tumors and multiple recurrences (up to 60 – 70 percent) of tongue cancer, cancer of oral mucosa, lower-lip cancer, intradermal metastases of melanoma, and other tumors [6, 7].
Endoscopic PDT yields good clinical and economic results. In this case, PDT makes it possible to recover lumen of a tumor-obturated esophagus, trachea, and large bronchi. Endoscopic PDT can treat other tumor-stricken internal organs. For example, it can be used in the treatment of hard-to-get-at tumors localized in the pancreaticoduodenal area and common hepatic duct .
Hence, PDT advantages are as follows:
1. Photodynamic therapy is applied when surgery is contraindicated because of the tumor spread and serious associated diseases. Photodynamic therapy is targeted at tumor cells, and it causes no damage to healthy tissues. Due to this, when PDT has destroyed a tumor, normal cells begin to propagate and fill the organ’s frame. This is of special importance for PDT of thin-walled and tubular organs (such as the stomach, colon, esophagus, trachea, bronchi, and bladder). Photodynamic therapy allows avoiding the organ wall perforation. Thus, the cancer patient with nonresectable tumor has a chance for treatment with use of PDT.
2. Photodynamic therapy produces a targeted effect. A photosensitizer is selectively accumulated in a tumor, and it is rapidly eliminated from healthy tissues that surround the tumor. Due to this, red light selectively damages the tumor, whereas surrounding tissues remain intact.
3. Photodynamic therapy avoids the systemic effect on the human being (in the case of chemotherapy of tumors, this effect does take place). Photodynamic therapy treats an area exposed to light. As a result, the patient is not subjected to an unwanted systemic effect. This makes it possible to prevent the patient from all side effects, typical of chemotherapy (such as nausea, vomiting, stomatitis, loss of hair, and inhibition of hematopoiesis).
4. Photodynamic therapy is cost-effective. For a majority of patients, PDT is a noninvasive or minimally invasive method. It is also a tolerant, local, and inexpensive technique, which can treat a variety of malignant tumors (primary tumors, recurrent tumors, and metastatic tumors).
The Ministry of Health of Russia analyzed the results of PDT application in Moscow Medical Centers. Photodynamic therapy was employed to treat malignant tumors of the skin, breast, oral mucosa, tongue, lower lip, larynx, lung, esophagus, stomach, bladder, and rectum. From 1992 to 2001, PDT was used to treat more than 1600 tumors in 408 patients. Most of the patients had been treated earlier with routine methods (such as surgery, radiotherapy, and combined treatment). Some of the patients had not been treated earlier owing to serious age-related and associated diseases. The rest of the patients received palliative PDT. They had extended obturating tumors of the esophagus, trachea, colon, large bronchi, and the cardia. Photodynamic therapy was performed to recanalize stenosed organs and to improve the quality of life.
Follow-up studies had been made for 2 months to 9 years. Photodynamic therapy produced a beneficial effect in 94.4 percent of the patients. Of these, 56.2 percent showed a complete tumor resorption, and 38.2 percent showed a partial tumor resorption.
Photodynamic therapy is an advanced therapeutic technique, which is employed in Russia with success. At present, new photosensitizers and optical sources are being developed for PDT and fluorescent diagnosis. Photodynamic therapy is a promising, cutting-edge, and cost-effective method for treatment of malignant and nonmalignant diseases. To disseminate information about this technique, PDT-oriented workshops and schools should be arranged for physicians.
- Spikes J.D. The origin and the meaning of the term “photodynamic” (as used in “photodynamic” therapy, for example) // J. Photohem. Photobiol. – 1991. - Vol. 9. - P. 369-374.
- Stranadko E.Ph., Ponomarev G.V., Meshkov V.M. et al. The first experience of Photoditazine clinical application for photodynamic therapy of malignant tumors. In Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy IX, T.J.Dougherty, Editor // Proc. SPIE. – 2000. - Vol. 3909 (2000). – P. 138-144.
- Reshetnikov A.V., Shvets V.I., Ponomarev G.V. In Advances of Porphyrin Chemistry, O.Golubchikov, Editor // St.Petersbourg: Research Institute for Chemistry of St.Petersbourg State University. - 1999. - Vol. 2. - Chapter 4. - P. 70-114.
- Ivanov A.V., Reshetnikov A.V., Ponomarev G.V. One more PDT application of chlorin e6. In Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy IX, T.J.Dougherty, Editor // Proc. SPIE. -2000. - Vol. 3909 (2000). P. 131-137.
- Riabov M.V., Stranadko E.Ph., Volkova N.N. Photodynamic therapy of locally spread basal-cell skin cancer // J. Laser Medicine. – 2002. – Vol. 6, ¹ 1. – P. 18-24.
- Vakulovskaya E.G., Shental V.V. Photodynamic therapy and fluorescent diagnosis of patients with breast cancer using domestic photosensitizers // J. Laser Medicine. – 2002. – Vol. 6, ¹ 1. – P. 25-27.
- Markichev N.A., Geinitz A.V., Yeliseenko V.I., Stranadko E.Ph. et al. Photodynamic therapy of tongue malignant tumors // J. Laser Medicine. – 2002. – Vol. 6, ¹ 1. – P. 13-17.
- Stranadko E.Ph., Meshkov V.M., Vasilenko Yu.V. et al. Photodynamic therapy of the major papilla duodeni // J. Laser Medicine. – 2002. – Vol. 6, ¹ 1. – P. 9-13.