Дата публикации: 08 октября 2021
Автор(ы): Yelena FILONENKO
Публикатор: Научная библиотека Порталус
Источник: (c) Science in Russia, №4, 2012, C.4-9
Номер публикации: №1633680983

Yelena FILONENKO, (c)

by Yelena FILONENKO, Dr. Sc. (Med.), Rehabilitation Department head, Herzen Research Oncological Institute, Moscow, Russia


The World Health Organization (WHO) points to a rising mortality rate caused by oncological diseases. In many countries, Russia including, only a negligible part of malignancies is diagnosed at an early stage when therapy is most effective. That is why high-tech methods of early diagnostics and treatment are a hot issue in present-day medicine. One such method is fluorescent diagnostics (FD) and photodynamic therapy (PDT) of tumors, a method that has already validated itself and shown good results.


Even though these methods have been adopted by practical medicine but in the past few decades with the advent of laser, the very idea of using the photochemical effects of various medical drugs was born centuries ago. For one, such photochemical effects were put to use in India, Egypt and China in treating vitiligo, or piebald skin-a malady causing abnormal pigmentation of some patches of the skin.


How does the photodynamic effect work? Its action is based on the capability of certain medical drugs

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(photosensitizers) of getting selectively accumulated in tumoral issue; combined with luminous radiation, it can initiate, depending on the radiation wavelength and power, two kinds of reactions: fluorescence (10-9 to 10-6 s photoluminescent glow) or else damage and/or destroy cancer cells by a chain of photochemical reactions triggered in the presence of oxygen. We might as well note here that photosensitizers are substances capable of absorbing light and inducing chemical reactions in biological tissues, the reactions that otherwise do not take place in the absence of such agents.


In his work published in 1900 Oscar Raab gave the first detailed description of the photosensitization effect. His work is the reference point for the present-day theoretical and experimental studies of this phenomenon. As a medical student at Munich University, he conducted research under the guidance of Professor Hermann Topeiner. O. Raab found that paramecia (infusoria), if put into a low-concentration solution of acridine or other dyes, perish upon subsequent solar insolation (though such dyes are chemically inert in the dark). Topeiner appraised highly this discovery-and he thought that this effect would have practical applications in medicine. Later he gave impetus to the development of this line of research. He introduced the term "photodynamic action" much in use today.


In 1903 Hermann Topeiner and Albert Jesionek of the Munich dermatological clinic published a fact sheet on the use of the eosine dye and light in treating herpes, psoriasis and skin cancer. Two years after, they started using yet another dye, fluorescein, as a photo-sensitizer.


Followup studies of the photodynamic effect (oxidation of biologically significant molecules in visible light in the presence of molecular oxygen and photosensitizer) gave birth to a new research line in medicine, the photodynamic therapy (PDT) of malignancies.

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Yet another finding came in the 1920s: neoplasms were shown capable of accumulating porphyrines* under the effect of UV radiation. Yet another important step in cancer diagnosis and therapy: in 1924 Albert Polikard, France, found endogenic porphyrines capable of accumulating in tumors of animals. These dyes fluoresced when exposed to light in the visible region of the spectrum. Then in 1942 two German research scientists, H. Auler and G. Banzer,


* Pigments widespread in living nature. As part of hemoglobins, myoglobins, cytochromes, chlorophyls and vitamins, porphyrines are implicated in essential biological processes.-Ed.

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registered red fluorescence in initial and secondary cancers in rats upon hypodermic and intramuscular injection of hematoporphyrine (formed in the process of hemoglobin metabolism).


The present stage of research began in the 1960s as Samuel Schwarz, Richard Lipson and colleagues (USA) demonstrated: tumors in patients, upon administration of a hematoporphyrine derivative (obtained by acetylation and reduction of a porphyrine mixture) started fluorescing. A wide use of PDT techniques began in 1978 as Thomas Dougherty (USA) reported positive results of such therapy in 25 patients with primary, relapsing and metastatic cancers of the skin.


In Russia, in spite of many years of experimental research, this problem was addressed by clinicians as late as 1992 when Dr. Andrei Mironov of the Moscow Institute of Fine Chemical Technology created a pharmacological form of photohem, the first domestic photosensitizer, of the group of hematoporphyrine derivatives. Clinical tests of this preparation were carried out at our research institute and at the State Research Center of Laser Medicine.


In 1994 clinical tests of a second generation photosensitizer, the photosense, were launched. This medicine, which is a sulphonated aluminum phthalocyanin, was created at the Moscow Research Institute of Organic Semiproducts and Dyes by RAS corresponding member Georgi Vorozhtsov and Dr. Yevgeny Lukianets. In 1999 clinical tests began of another preparation, alasense, synthesized by the same two researchers from 5-aminolevulinic acid. Yet another preparation, radachlorine, was adopted in clinical practice in 2002. It was synthesized from chlorin E6 by Andrei Reshetnikov, a doctoral candidate, at the Rada-Farma Company. In 2004 came clinical tests of photodithasine developed at the Beta-Grand Company, by Gely Ponomaryov, Dr. Sc. (Chem.), Institute of Biomedical Chemistry named after V. Orekhovich, RAMS, Moscow.


Our Institute began tests in the field of fluorescent diagnosis and photodynamic therapy about 30 years ago, and the first results were on hand in 1984. Clinical studies have been in progress there since 1992. By now treatment procedures have been developed on the basis of the above preparations, and recommendations drawn up. We have prepared practical aids for clinicians and a course for training practitioners in this field. The introduction of new procedural approaches has become possible thanks to the creation of home-developed diagnostic and therapeutic facilities. Several thousand patients at different stages and localization of tumors have been worked up at our clinic with the use of fluorescent diagnostics (FD) and PDT


PDT can be used both independently and in combination with conventional procedures (surgery, radio-and chemotherapy). Combined therapy improves the results of radical and palliative (mitigating) treatment of the worst cases. Depending on the stage, nature and form of a malignancy, different strategies of laser irradiation have been worked out: uni-and multipositional, invasive and noninvasive as well as other techniques.


As we have already said, FD and PDT are based on the action of photosensitizers capable of selective accumulation in tumoral tissue both in light and at laser exposure resulting in light quantum emission causing fluorescence or else producing cytotoxic substances, above all singlet oxygen (1O2)* and other active radicals that, built up in tumors, destroy the vital structures of tumor cells and kill them in the end. Apart from the direct phototoxic action on malignant cells, the PDT-induced cancer destruction mechanism involves other effects. Thus, it interferes with the blood supply of tumoral tissues by damaging the endothelium and by thrombosis of blood vessels; furthermore, it initiates reactions involving cytokins (signal molecules), interleukins**, and also activates macrophages and leucocytes (white blood cells). The cumulative action of these factors results in tumor necrosis (death).


The PDT immunostimulating mechanisms have been drawing much attention lately. The experience of our research institute shows this method to be activating the neutrophilic and other immunity factors.


So, FD and PDT are remarkable for the multistage diagnostics and treatment procedures. These methods involving multicomponent responses to cancer therapy have prodded experts to elaborate new approaches in studying photosensitizers at our clinic.


To map out optimal strategies for FD and PDT with the use of home-produced photosensitizers of different classes, our research institute offers an adequate program. It envisages multipronged studies, specifically, into the kinetics of tissue and interstitial distribution of new preparations in oncological cases, thus


* Active form of molecular oxygen that readily enters into redox reactions.-Ed.


** Cytokins synthesized largely by leucocytes; interleukins are part of the immune system.-Ed.

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making it possible to optimize therapeutic methods and their targeted action, for PDT is most effective if we know in what structures of a tumoral node a given preparation is accumulated during a treatment session. The presence of a photosensitizer in cancer cells damages them directly, and its buildup in a tumor stroma (framework) with its many blood vessels causes an ischemic necrosis through thrombosis and destruction of vessels. These questions had to be tackled for a correct PDT strategy, which we did.


The photohem preparation accumulates to a maximum in tumoral tissue 24 to 48 hours after its intravenous injection. Since the photosensitizer is accumulated in higher amounts in the stroma than in cancer cells, it induces an ischemic necrosis of the stroma. Data on the low presence of the preparation in the walls of sound blood vessels attest to a small risk of an ischemic pathology within the zone of luminous radiation with the use of standard modes of laser irradiation.


Yet in the case of photosense-mediated PDT an ischemic necrosis of the tumor predominates. Maximum levels of fluorescence in tumoral tissue were registered 2 to 8 hours upon intravenous administration, which fact indicates the greatest damage of the neoplasm during a PDT session. The presence of significant amounts of photosense for a week after intravenous injection points to the possibility of further PDT sessions. But the identical presence of photosense in the tumor and in the walls on nonaffected blood vessels next to the malignancy 1 to 2 hours after administration may damage vessels and induce ischemic changes of tissues in the field of laser irradiation.


PDT based on chlorine E6 preparations caused predominantly an ischemic necrosis of tumors. The optimal time of the treatment session is 3 to 8 hours upon intravenous injection due to a maximum in the concentration of such preparations in malignancies. But the identical presence of the photosensitizer in the tumor and walls of sound vessels 3 to 4 hours upon intravenous administration may damage these vessels within the bounds of the entire field of laser radiation and induce ischemic lesions of sound tissues.


We found that alasense-induced protoporphyrine IX (PPIX) is the only photosensitizer accumulating largely in cancerous cells and resulting in direct cytotoxic effects during PDT.


So, we offer new methodic approaches in designing medical technologies both respective optimal diagnostic schedules and therapy for each photosensitizer. As we demonstrated, some photosensitizers (like photohem, E6 chlorine-based preparations, alasense-induced PPIX) are quickly eliminated from tumoral tissues, and so they can be used in one and many PDT treatment courses, while others (like photosense) stay in for a long time and make possible follow-up sessions upon single introduction of the preparations. We also found what effects are realized in PDT involving different preparations-either an immediate destruction of tumoral cells or an ischemic necrosis as a consequence of decomposition of the tumor stroma rich in blood vessels. These data are incorporated into patented FD and PDT treatment procedures that have shown their high efficiency.


Complete tumoral regression has been achieved in precancer and initial cancer treatment: in 64.6 percent cases of malignancies affecting the mucous membrane of the mouth and tongue; in 72.6 percent cases of stomach carcinomas, and in 77.1 percent cases involving esophageal cancer. For central lung cancer the fig-

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ure is 86.5 percent, for skin cancer-99.6-100 percent, and 84-100 percent for cervical carcinoma.


The same medical technologies have proved effective in adjuvant (follow-up) therapy or intraoperational action in cases involving a high risk of post-surgical tumor relapses. Thus, in patients having secondary cancers of the brain after surgery supplemented with intraoperational FD and PDT, secondary cancers were detected in 4.2 percent cases (30.3 percent in the control group) in a 1 to 6 months time stretch); in cases of inorganic retroperitoneal carcinomas the recurrence rate after surgery combined with PDT was equal to 12 percent (against the ordinary rate of relapses ranging between 50 to 80 percent).


The placebo PDT technologies allowed to increase the life quality and span of the worst oncological cases. Prolonged PDT treatment of patients affected with intradermal metastases (secondary cancers) of mammalian cancer and melanoma gave 39.3 and 38 percent cases of complete regression, respectively, and partial regression, in 46 and 52.4 percent of cases. Multiple PDT treatment sessions restored the natural diet in 100 percent patients having stenosing esophageal carcinoma.


Alasense-mediated fluorescent diagnostics helps spot more exactly the boundaries of malignant tumors in planning PDT-aided surgery and detect hidden foci of early primary and superficial cancer of the skin and mucous membrane of hollow organs (esophagus, stomach, urinary bladder). The sensitivity of alasense-assisted diagnostics for cancer of upper respiratory tracts was as high as 100 percent, and for tumors of the upper stretches of the gastrointestinal tract, as much as 96 percent. FD made it possible to detect the hidden foci of precancer, initial cancer and superficial relapses of skin cancer in 25.5 percent of patients. For tumors of the upper respiratory tract the figure was 19.4 percent; for hidden foci of metastatic lesions of the pleura, 57.2 percent; and for peritoneal cancer, the diagnostics ratio was 15.5 percent.


FD and PDT technologies developed at our research institute have been adopted at other medical institutions. We are running a college of further education for experts specializing in this field. More than 200 medical doctors from different towns of Russia, former Soviet republics and foreign countries have taken further education classes.


To upgrade the method of photodynamic therapy we should search for new photosynthesizers exhibiting higher photoactivity, targeted action and excitation capability in the near infrared region of the spectrum. Furthermore, we should create high-sensitivity and reliable diagnostic and therapeutic apparatuses.


For designing and introduction of fluorescent diagnostics and photodynamic therapy technologies in practical oncology the collective of authors headed by Yelena Filonenko has been awarded a federal government prize in the field of science and technology for 2011.



Опубликовано на Порталусе 08 октября 2021 года

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