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THE STATE OF SOME CYTOKINS OF THE IMMUNE SYSTEM IN STUDYING THE RESULTS OF COHERENT IMMUNOTHERAPY IN PATIENTS _WITH OVARIAN CANCER_
Kamishov Sergey Viktorovich
MD, PhD, senior researcher, chemotherapeutist Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry
of Health of the Republic of Uzbekistan, Tashkent, Uzbekistan
СОСТОЯНИЕ НЕКОТОРЫХ ЦИТОКИНОВ ИММУННОЙ СИСТЕМЫ В ИЗУЧЕНИИ РЕЗУЛЬТАТОВ СОПРОВОДИТЕЛЬНОЙ ИММУНОТЕРАПИИ У БОЛЬНЫХ РАКОМ
ЯИЧНИКОВ
Камышов Сергей Викторович,
кандидат медицинских наук, старший научный сотрудник отдела химиотерапии Республиканского специализированного научно-практического медицинского центра онкологии и радиологии Министерства Здравоохранения Республики Узбекистан, Ташкент
АННОТАЦИЯ. Рак яичников (РЯ) занимает стабильно 3 -е место в структуре онкогинекологической патологии. Смертность от РЯ превышает смертность от рака шейки матки и тела матки вместе взятых, несмотря на достигнутые успехи в диагностике и лечении. Бессимптомное течение заболевания на ранних стадиях, приводящее к позднему обращению к врачу, а, следовательно, к выявляемости уже с распространенными стадиями заболевания (до 70%) приводит к высокой смертности пациенток [11,15]. Более того, нарушение баланса в системе цитокинов рассматривается как важный механизм развития многих патоло-
гических процессов, в том числе и онкологических. Как известно, все составляющие современного комплексного лечения больных со злокачественными процессами, в частности раком яичников являются факторы, которые инициируют иммуносупрессию в основном по клеточному типу, что крайне опасно, так как опухоль в свою очередь также использует механизмы супрессии для уменьшения ответа организма на ее наличие. Развивается и имеется ряд научных подтверждений, согласно которым в процессе неогенеза происходит нарушение баланса между продукцией пронеопластических (IL-6, IFN-a/ft), антинеопластических (IL-2, TNF-a), и других регуляторных цитокинов. К тому же, несмотря на усовершенствование методов диагностики, лечение рака яичников остается одной из актуальных проблем онкологии, что обусловлено неудовлетворительными результатами терапии этого заболевания [12,14]. Течение опухолевого процесса сопровождается формированием эндотоксикоза и вторичной иммунологической недостаточности. Следует отметить, что эндотоксикоз это сложный, многокомпонентный процесс, который обусловлен накоплением в тканях и биологических жидкостях эндотоксических субстанций в условиях снижения физиологических процессов детоксикации. Проведение при этом химиотерапии способствует дальнейшему нарастанию эндогенной интоксикации, угнетению иммунокомпетентности организма, что осложняет течение основного онкологического заболевания, а иногда, при развитии органных и системных нарушений, ограничивает возможности для проведения адекватного курса противоопухолевого лечения [1,4,6,7]. Несмотря на высокую чувствительность опухоли при РЯ к воздействию современных цитостатических препаратов, зачастую возможности противоопухолевого лечения ограничены, что связано с их высокой токсичностью и выраженностью метаболических нарушений на уровне целостного организма [1,3]. Для повышения возможности проведения своевременной химиотерапии большое значение придается методам, приводящим к снижению эндогенной интоксикации и повышению иммунорезистентности организма [9,11,12,13]. К таким методам относятся плазмаферез и экстракорпоральная иммунофармакотерапия [4,6,7]. Детоксикаци-онный эффект плазмафереза заключается не только в непосредственном удалении из кровотока токсинов, ксенобиотиков, биологически активных веществ и других различных патологических субстанций, а также в активном дренирующем воздействии на межклеточное пространство, деблокировании клеточных рецепторов органов и систем физиологической детоксикации, которые приводят к усилению механизмов элиминации токсинов [2,3,5,9]. В связи с вышесказанным, иммунотерапия РЯ является относительно новым направлением, при котором подходы к её осуществлению, конкретные методики, сроки, возможность комбинирования с другими методами лечения остаются недостаточно изученными и разработанными, и естественно, недостаточно описанными в литературе.
Ключевые слова: рак яичников, цитокины, интерлейкины, иммунная система, иммунотерапия
ANNOTATION. Ovarian cancer (OC) occupies a stable 3rd place in the structure of oncogynecological pathology. Mortality from OC exceeds mortality from cervical cancer and uterine body combined, despite the advances in diagnosis and treatment. The asymptomatic course of the disease in the early stages, leading to late treatment to the doctor, and, consequently, to detectability with already widespread stages of the disease (up to 70%) leads to a high mortality of patients. Moreover, the imbalance in the cytokine system is seen as an important mechanism for the development of many pathological processes, including oncological ones. As is known, all the components of modern complex treatment for patients with malignant processes, in particular ovarian cancer, are the factors that initiate immunosuppression mainly by the cellular type, which is extremely dangerous, since the tumor also uses suppression mechanisms to reduce the body's response to its presence . A number of scientific evidences are evolving, according to which in the neogenesis process there is a disbalance between the production of proneoplastic (IL-6, IFN-a / ft), antineoplastic (IL-2, TNF-a), and other regulatory cytokines. In addition, despite the improvement of diagnostic methods, the treatment of ovarian cancer remains one of the urgent problems of oncology, which is caused by unsatisfactory results of therapy of this disease. The course of the tumor process is accompanied by the formation of endotoxicosis and secondary immunological failure. It should be noted that en-dotoxicosis is a complex, multicomponent process that is caused by the accumulation in the tissues and biological fluids of endotoxic substances in conditions of a decrease in the physiological processes of detoxification. Carrying out chemotherapy promotes further growth of endogenous intoxication, suppression of the body's immunocompe-tence, which complicates the course of the main oncological disease, and sometimes, with the development of organ and systemic disorders, limits the possibilities for an adequate course of antitumor treatment [1,P. 169; 4, P. 4275; 6, P. 5896; 7,P.3591]. Despite the high sensitivity of the tumor to OI to the effects of modern cytostatic drugs, often the possibilities of antitumor treatment are limited, which is associated with their high toxicity and the severity of metabolic disorders at the level of the whole organism [1, P. 169; 3, P. 2246]. To increase the possibility of timely chemotherapy, great importance is attached to methods leading to a decrease in endogenous intoxication and an increase in the body's immunorefense [9, P. 501]. Such methods include plasmapheresis and extracorporeal immunopharmacotherapy [4, P. 4275; 6, P. 5896; 7, P.3591]. The detoxification effect of plasma-pheresis is not only the direct removal of toxins, xenobiotics, biologically active substances and other various pathological substances from the bloodstream, but also in the active drainage action on the intercellular space, the deprotection of the cellular receptors of organs and the systems of physiological detoxification, which lead to an intensification of toxin elimination mechanisms [2,P. 1934; 3, P. 2246; 5, P.4275; 9,P. 501 ]. In connection with the foregoing, immunotherapy is a relatively new direction in which approaches to its implementation, specific techniques, timing, the possibility of combining with other methods of treatment remain insufficiently studied and
developed, and naturally, insufficiently described in the literature. Key words: ovarian cancer, cytokines, interleu-kins, immune system, immunotherapy.
Materials and methods of the research. Patients with ovarian cancer of T2-3N0-1M0 stages (II-III clinical stages) who were on treatment in oncogynecology and chemotherapy departments of Republican examined.
The aim of the research. To study the state of some cytokines of the immune system in patients with ovarian cancer II-III stage in the framework of accompanying immunotherapy.
Materials and methods of the research. Patients with ovarian cancer of T2-3N0-1M0 stages (II-III clinical stages) who were on treatment in oncogynecology and chemotherapy departments of Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry of Health of the Republic of Uzbekistan were examined. In accordance with the objectives of the study, patients with OC are randomized to the following groups: the 1st group - 32 practically healthy individuals; the 2nd group - 34 patients with OC to PCT; Group 3 - 40 patients with OC after PCT without immunotherapy; the 4th group - 44 patients with OC after PCT in combination with extra-corporeal immunopharmacotherapy (EIPHT); 5th group - 46 patients with OC after PCT in combination with extracorporeal immunopharmacotherapy and plasmapheresis (EIPHT + PPh). All patients underwent clinic-laboratory blood tests, which included the study of a general analysis of blood and urine, biochemical parameters, and blood coagulation. Combined therapy in adjuvant or neoadjuvant regimen was carried out in patients with OC, including polychemotherapy with the cisplatin regimen of 75 mg / m2 + cyclophosphamide 1000 mg / m2 for 1 day for 4-6 courses 1 time in 3 weeks and surgical treatment in the volume of a radical operation. Chemotherapy was performed in both adjuvant and neoadjuvant regimens. EIPHT and EIPHT + PPh in patients with OC using immunomodulators were carried out during the period of radiotherapy and chemotherapy in the hospital. The method of extracorporeal immunopharmacotherapy (EIPHT) was carried out with the aim of reducing the toxic manifestations after carrying out polychemotherapy and increasing the im-munorefense of the organism. EIPHT was performed by exfusion of 500-1000 ml of autoblood in sterile "Gemakon" or "Terumo" containers and its centrifugation at 3000 rpm for 30 minutes. 50-80 ml of the supernatant of the blood plasma were removed. Then the obtained leukotrombomass and erythrocytic mass were incubated with an immunotropic drug in a total dose of 30 mg at 37 ° C for 60-100 min, with the subsequent return of the conjugate to the circulatory system of the patients. To stimulate the cell link of immunity, an immunotropic drug was used - cycloferon, Russia. Immuno-logical studies included a serum evaluation of the main cytokines of the immune system. Serum levels of cytokines (IL-6, IFN-y, TNF-alpha) were determined by ELISA using the test systems of the firm "Human" (Germany) in the dynamics of complex treatment. During the statistical analysis of the data presented in the
work, the results of the research were entered into databases prepared in Microsoft Excel XP. Numerical (continuous) values were presented as mean arithmetic mean values and mean error (M ± m). A comparison of the quantitative traits was carried out with the help of the Student's test, for continuous variables - the paired Student test. As a boundary comparative criterion for the statistical significance of reliability, p <0.05 was assumed.
The obtained results and their discussion. The
interferon system is an integral part of the immune system that provides coordination of the proliferation, differentiation and activation of effector cells of immunity. An evaluation of the functional state of the interferon system is the study of the content of the interferons themselves [8]. We studied IFN-y, which refers to the cytokines produced by the TX1 -type. IFN-y has antiviral and tumorigenic activity, activates monocytes and macrophages, natural killers (cytotoxicity), proliferation and differentiation of T-lymphocytes, suppresses tumor growth, proliferation, proliferation of B-lymphocytes. By its nature, IFN-y is a potent im-munostimulant and inducer of nonspecific body defense [7,P. 3591; 8, P.3399]. The study of IFN-y revealed a statistically significant increase in its content in all groups of patients with ovarian cancer compared with the 1 st group of healthy individuals. The analysis showed that serum IFN-y levels were statistically increased in all groups of patients when compared with each other. The analysis showed that IFN-y was increased by 6.1 times in the 2nd group of patients before PCT, in the 3rd group after PCT without immunotherapy - by 27 times, in the 4th group after PCT in the complex EIPHT - in 8.2 times and in the 5 th group of patients after PCT in the complex EIPHT + PPh - 8.8 times. Consequently, the highest level of IFN-y in the serum of peripheral blood was detected in the group of patients after PCT in the complex EIPHT + PPh. Obviously, the use of EIPHT + PPh complex has a positive effect on the immune system, which is expressed in the immunomodulatory effect of IFN-y, which is an immune cytokine. The data obtained by us agree with the data of the literature, where the positive effect of the EIPHT in the complex of PPh is quite clearly demonstrated, and the use of cycloferon, which is an immuno-modulating drug that effectively influences cellular immunity due to the induction of cellular interferon-gamma, has proved to be important. As shown above, carrying out PCT increases the content of proinflamma-tory cytokines in the blood. It should be noted that this process occurs against a background of increasing concentrations of IFN-y, which inhibits tumor angiogene-sis [10, P. 3399]. According to our data, it is clear that when the PCT of patients with OC immunotherapy is included in the complex, a significant increase in the serum concentration of IFN-y is observed. Cytokines with systemic effects - IL-ip, TNF-a and IFN-y - play a key role in the entire spectrum of cytokines, including those secreted by the tumor. The study of IL-6 revealed a statistically significant increase in all groups of patients with cervical cancer compared with group 1 of
healthy individuals. Analysis of the studies showed that serum IL-6 levels were statistically increased in all groups of patients when compared with each other. A comparative analysis of IL-6 levels between the groups revealed that when compared with group 1, the level of IL-6 was increased 6.8 times in the second group of patients before PCT, in the 3rd group after PCT without immunotherapy - in 8 , 4 times, in the 4th group after PCT in the complex EIPHT - 4 times and in the 5th group of patients after PCT in the complex EIPHT + PPh - 2.2 times. It has been shown that after PCT without the use of immunotherapy in the complex it is manifested by increased values of IL-6. IL-6 is an important diagnostic index of malignancy of the oncological process. As is known, a high level of IL-6 can interfere with effective immunotherapy [7,P. 3591]. In the EIPHT and EIPHT + PPh complex in PCT complex in patients with OC with the presence of tumor intoxication, a positive dynamics of the main parameters of the immune system, as well as a decrease in the level of serum pro-inflammatory cytokines, some of which have a growth-stimulating effect, for example, IL-6 [8, P. 3399]. It should be noted that carrying out PCT aggravated the existing deviations from the average level of cytokines of a group of practically healthy persons and patients to PCT. The peculiarity of patients with OC on the background of PCT was the progressive suppression of the mechanisms of cytokine regulation during chemotherapy. Consequently, an increase in proin-flammatory cytokines in the serum of peripheral blood of patients with OC was observed. Thus, cytokines in OC were characterized by an increased content of the main pro-inflammatory cytokines. Inclusion in the complex of accompanying treatment of EIPHT and EIPHT + PPh, is one of the ways to reduce endogenous intoxication during antitumor drug therapy. Application of the abovementioned immunotherapy methods, according to modern literature, can serve as a modifier of chemotherapy treatment, since its tolerance directly depends on the functional state of the organs and systems of physiological detoxification of the organism [6, P. 5896], and, not least, the immune system. Moreover, tsikloferon possesses a pronounced ability to induce the main interferons of the body, which play an important role in the formation of an adequate immune response. Therefore, the conducted studies showed that the most effective in reducing the side effects of chemotherapy in the complex treatment of patients with OC stage II-III, as well as in improving the subjective state of patients and their quality of life, immunotherapy schemes including the use of EIPHT and EIPHT + PPh, which reduce the main clinical manifestations of the toxicity of chemotherapy, improves the subjective state of the patient. Thus, the use of EIPHT in the complex therapy of oncogynecologic diseases with the use of cycloferon makes it possible to increase the clinical efficacy of patients. The EIPHT method developed by us has great prospects in oncological practice in connection with the possibility to remove the consequences of cancer and chemoradiation intoxication, and also to activate our own system of antitumor protection of the body, which should positively affect the outcome of the disease and
lead to an increase in the quality and life span of the patient.
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