CC BY
31UDC: 618.14-006.327
ANTIOXIDANT SYSTEM IN THE PATHOGENESIS OF TUMOR DISEASES (BY THE EXAMPLE OF FIBROIDS AND
UTERINE CANCER)
A.A. Firman1, A.V. Efremov1, O.J. Uzakov2
!INCO, the Hyperthermia research institute, Novosibirsk, Russian Federation international Higher School of Medicine, Bishkek, Kyrgyz Republic
Abstract
The aim of the study was to study the activity of the antioxidant system of the body in cancer patients, based on the content of fat-soluble antioxidants. 436 women were examined: 101 patients diagnosed with uterine fibroids; 290 women with uterine body cancer and 45 healthy women as controls. The content of -carotene, retinol and -tocopherol in blood serum was analyzed. It has been shown that in uterine cancer, unlike uterinefibroids, there is a more pronounced inhibition of the antioxidant system activity, expressed in a significant decrease in the levels of beta-carotene, retinol and -tocopherol in the blood. Conclusion: the inhibition of the antioxidant system activity in the mechanisms of development of tumor growth is beyond doubt.
Keywords: uterine cancer, uterine fibroids, antioxidants, -carotene, retinol, -tocopherol.
ШИШИК ООРУЛАРЫНЫНПАТОГЕНЕЗИНДЕГИ АНТИОКСИДАНТТЫК СИСТЕМА (МИОМА ЖАНА ЖА ТЫН РАГЫНЫН МИСАЛЫНДА)
А.А. Фирман1. А.В. Ефремов1, О.Ж. Узаков2
1Сибирь гипертермия илим изилдее институту АКэУ Новосибирск, Россия Федерациясы
2Эл аралык Жогорку Медициналык Мектеби, Бишкек, Кыргызстан Аннотация
Изилдеенун максаты майды эритуYЧY антиоксиданттардын мазмунуна негизделген рак менен ооруган организмдин антиоксиданттык системасынын активдYYЛYгYн изилдее болгон. 436 аял текшерилди: 101 жатын денесинин миомасы менен ооруган, 290 жатын денесинин рагы менен ооруган жана 45 дени сак аял контроль катары изилденген. Кандын сывороткасындагы -каротиндин, ретинолдун жана -токоферолдун курамына анализ жасалган. Жатындын рак оорусунда, жатын денесинин миомасынан айырмаланып, антиоксиданттык системанын активдYYЛYгYHYн айкыныраак твмвндвшY аныкталган, канда ал -каротиндин, ретинолдун жана а-токоферолдун децгээлинин олуттуу темендешY менен керсетYлет.
Корутунду: антиоксиданттык системанын активдYYЛYгYH твмвндвтYY шишиктин есYШYHYH механизмдеринде ку.мен туудурбайт.
Ачкыч свздвр: жатын рагы, жатын денесинин миомасы, антиоксиданттар, -каротин, ретинол, а-токоферол.
АНТИОКСИДАНТНАЯ СИСТЕМА В ПАТОГЕНЕЗЕ ОПУХОЛЕВЫХ ЗАБОЛЕВАНИЙ (НА ПРИМЕРЕ МИОМЫ
И РАКА МАТКИ)
А.А. Фирман1. А.В. Ефремов1, О.Ж. Узаков2
!ЛНО НИИ гипертермии. Новосибирск, Российская Федерация 2Международная высшая школа медицина, Бишкек, Кыргызстан
Аннотация
Целью исследования было изучение активности антиоксидантной системы организма у онкологических больных на основании содержания жирорастворимых антиоксидантов. Обследовано 436 женщин: 101 пациентка с диагнозом миома тела матки, 290 женщин с раком тела матки и в качестве контроля 45 здоровых женщин. Анализировалось содержание -каротина, ретинола и -токоферола в сыворотке крови. Показано, что при раке матки, в отличие от миомы тела матки, определяется более выраженное угнетение активности антиоксидантной системы, выражающееся в достоверном снижении уровней -каротина, ретинола и -токоферола в крови. Вывод: угнетение активности антиоксидантной системы в механизмах развития опухолевого роста не вызывает сомнений.
Ключевые слова: рак матки, миома тела матки, антиоксиданты, -каротин, ретинол, -токоферол.
Introduction
Role of oxidative stress in the molecular and cellular mechanisms of tumor growth has been of great scientific interest in recent years among a large number of domestic and foreign researchers. But at the same time, the problem of free radical neoplastic transformation of body cells remains understudied.
In the second half of the twentieth century, academician Emanuel N. M. [14] was the first to formulate a hypothesis that suggested that free radicals are actively involved in the malignant transformation of cells and the progression of tumor growth. Later, it received worldwide recognition [4, 12, 13, 19, 24]. According to modern views, oxygen and nitrogen radicals and the free radical oxidation reactions of lipids and
proteins initiated by them can be considered as a trigger for neoplastic cell transformation, causing spontaneous or induced oncogenesis. Particular attention in this regard is attracted by scientific works, where researchers, taking the kinetic parameters of tumor growth as a basis, suggest that free radical reactions are of great importance not only in the primary mechanisms of tumor transformation, but also in the further progression of the tumor growth [21, 22 ].
The use of modern biochemical, radioisotope and NMR methods for studying the level of radicals and their metabolites in tumor tissues confirmed the hypothesis of an increase in free radical (peroxide) reactions at the initial stages of tumor formation and growth in a living organism. So, V.A.
Baraboy et al. [3], studying the dynamics of the accumulation of peroxide products (diene conjugates (DC), malondialdehyde (MDA)) and the activity of antioxidant enzymes (superoxide anion scavenger (SOD), catalase), revealed that the stages of the body's resistance to tumor growth correspond to a shift in the oxidative balance towards the activation of antioxidant systems associated with the regulation of the severity of the level of peroxidation reactions. At the same time, the opposite ratio of the components of the oxidation-reduction equilibrium is typical for the initial and final stages of oncogenesis.
In a number of works by Burlakova E.B. [4] it was found that changes in the antioxidant activity (AOA) of lipids in transplanted and induced tumors, both with the help of chemical carcinogens and with physical mutational exposure, correlate with changes in the parameters of the rate of tumor cell proliferation. It was found, for example, that the morphological growth of transplanted tumors proceeds with an increased lipids AOA, while that of induced tumors is accompanied by staged changes. Based on the experimental data of Burlakova E.B. [4] it was concluded that there is a "redistribution" of antioxidants from the internal organs to the tumor tissue in the dynamics of tumor growth. This fact is confirmed by the presence of a high level of AOA in the cells of the tumor tissue. The author suggests that this mechanism plays a leading role in the inactivation of lipid peroxidation reactions (LPO), which have low activity in the tissue material of tumors of various origins. These mechanisms, identified almost half a century ago, received brilliant confirmation in the future. It has been shown that, in addition to inhibition of LPO reactions, a high level of AOA protects
tumor cells from phagocytosis and cytotoxic action induced by reactive oxygen metabolites (ROM) [6, 19, 20].
The next highly active factor in the antioxidant defense in the body is non-enzymatic compounds classified by solubility into fat- and hydro soluble antioxidants.
Fat-soluble antioxidants include, first of all, fat-soluble antioxidant vitamins (a-tocopherol, retinol, b-carotene), as well as ubiquinone, sex hormones, etc. Water-soluble antioxidants are compounds containing sulfhydryl (SH-) groups (cysteine, glutathione, methionine), ascorbic acid, uric acid, etc. [7, 16, 20, 25].
The general mechanism of the antioxidant action of these compounds is due to their high donor (H+) properties and the ability to reduce peroxide radicals in the hydrophobic and hydrophilic phases of cell membranes [32]. Tocopherols have the highest activity among fat-soluble antioxidants [9, 18]. For example, a-tocopherol, interacting effectively with the products of free radical reactions, protects membrane lipids from oxidative degradation due to the formation of stable complexes between tocopherol molecules and fatty acid residues, as well as photochemical and photophysical interaction with ROM. a-tocopherol eliminates free radicals, reducing them into inactive forms. The reduction of a-tocopherol itself is carried out by the flow of protons from nicotinamide adenine dinucleotide NAD (H) and nicotineamide-adenine dinucleotide phosphate NADP (H) to the tocopheroxyl radical from the chain of antiradical inhibitors (reduced glutathione, e rgo thio nine as c o rb ate ) , wi th the participation of the corresponding reductases and dehydrogenases [17, 31].
Other important fat-soluble
compounds that ensure the normal vital processes are P-carotene and retinol [5]. Thus, the presence of conjugated bonds in the retinol molecule and the tendency to autoxidation substantiate the possibility of its participation in free radical reactions. Confirmation is the data on a decrease in the activity of Fe2+- and ascorbate-dependent LPO in retinol in microsomes and mitochondria of renal and hepatic cells in experimental animals [29, 30]. The content of the latter on a semi-synthetic diet without carotenoids and retinol causes a significant decrease in the activity of superoxide scavenger SOS, glutathione peroxidase, and the level of reduced glutathione in lung microsomes against the background of a significant increase in enzymatic and non-enzymatic LPO [28]. It has been shown that the additional intake of retinol and carotene leads to stabilization of the activity of free radical reactions in the body [27].
It remains unclear to what extent the content of fat-soluble antioxidants (P-carotene, retinol, a-tocopherol) in the blood serum of cancer patients reflects their antioxidant status at the level of the whole organism.
Goal of research: to study the activity of the antioxidant system of the body in cancer patients (as in the case of uterine cancer), based on the content of fat-soluble antioxidants.
Object and methods of research.
436 women were examined, of which the first group consisted of 101 patients with a diagnosis of uterine fibroids. In 63.4% of patients in this group, ultrasound revealed single myoma nodules, in 36.6% - multiple nodules. The overall size of the uterus corresponded to 5-6 weeks of gestation in 59.4% of patients, 7-9 weeks - in 41.6%. More than 50% of patients did not present
complaints typical for patients with uterine myoma; 30.6% noted painful menstruation, and 26.7% noted heavy and prolonged menstruation.
The second group included 290 women with uterine body cancer (UBC). According to the degree of tumor differentiation [11], the group consisted of 34.5% of patients with highly differentiated, 33.8% with moderately differentiated and 31.7% with poorly differentiated adenocarcinoma. The distribution by morphological stages of the disease showed that 67.6% of patients have stage I of the disease; 20.6% - II, 7.4% - III and 4.4% - IV.
The control group included 45 women who were the same age as the patients of the first and second clinical groups, but did not have a history of tumor diseases of the uterus and other internal organs. The age of UBC patients varied from 38 to 69 years; patients with myoma of uterine body - from 33 to 67 years; women in the control group - from 34 to 65 years.
All studies were performed in accordance with the Declaration of Helsinki of the World Medical Association "Ethical principles for medical research involving human subjects" and "Rules of clinical practice in the Russian Federation", approved by the Order of the Ministry of Health of the Russian Federation №266 dated June 19, 2003.
Analysis of the content of -carotene, retinol and -tocopherol in blood serum was carried out using high-pressure liquid chromatography (HPLC) on a domestic microcolumn chromatograph "Milichrom" [8]. As witnesses for fat-soluble vitamins, calibration solutions of the following standards were used: -tocopherol, retinol-acetate, and -carotene (Serva, USA). The content of fat-soluble vitamins was
calculated from the amplitude of the peaks obtained on the chromatogram, in terms of the standard and expressed in mg% for -tocopherol and p,g% for retinol and -carotene.
Research outcomes.
The study of the content of fat-soluble antioxidants showed that in the control group of women, the mean of -carotene concentration in the blood serum was 39.5 pg%, and the lower and upper limits of the standard values were 28.2 and 55.3 pg%, respectively.
In the first group of women examined
with a diagnosis of uterine fibroids, the "average" concentration of P-carotene was 28.72 p,g%, the values of the determined indicator were significantly (p < 0.05) lower by 27.3% of the "average" standard values.
In the second group of patients diagnosed with uterine cancer, the mean P-carotene content was 25.7 p.g%, which was also significantly (p<0.05) lower by 35.1% of the mean values of the normative indicators and did not differ from the values obtained in the group of women with uterine myoma (p>0.05). The results obtained are presented in Table 1.
Table 1. P-carotene content in the blood serum of patients with myoma and cancer of
the uterine body in comparison with t ie standard values (M±m).
Groups P-carotene (p,g %)
Control (n=45) 39,50 ± 3,07
Миома тела матки (n=101) Myoma of the uterus body 28,72 ± 1,98*
Рак тела матки (n=290) Cancer of the uterus body (n=290) 25,70 ± 2,34*
Note: * - p < 0.05 in relation to the control group
An individual analysis of the data obtained made it possible to identify the following patterns.
In the first group (uterine fibroids), the content of -carotene within the limits of standard values was detected in 53 patients (52.5%); values below the standard values were found in 48 examined women with uterine fibroids (47.5%).
In the second group of patients with uterine cancer, P-carotene concentrations that were within the limits of standard values were found in 101 patients (35.1%); values below the limit of standard values were found in 189 examined women (64.9%).
When testing the concentrations of
retinol in the control group of women, its mean content was determined to be 57.4 pg%, the lower and upper limits of the standard values for the specified fat-soluble vitamin were 39.89 and 69.61 ^g%, respectively.
In the group diagnosed with uterine myoma, the "average" concentration of the tested antioxidant was 46.1 pg%, the values o f the de te rmine d i ndi c ato r we re significantly (p<0.05) lower by 19.7% of the "average" standard values.
In the group of patients diagnosed with uterine cancer, the mean content of retinol was 38.4 ^g%, which was significantly (p<0.05) lower by 33.2% than the mean
values of the normative indicators and 1.2 with uterine fibroids.
times lower the mean concentrations of the The results obtained are presented in
determined vitamin in the group of patients Table 2.
Table 2. The content of retinol in the blood serum of patients with myoma and cancer of the uterine body in comparison with the standard values (M±m).
Groups Retinol (^g%)
Control (n=45) 57,4 ± 2,05
Uterine fibroids (n=101) 46,1 ± 1,63*
Uterine cancer (n=290) 38,4 ± 2,03*
Note: * - p < 0.05 in relation to the control group
An individual analysis of the data obtained made it possible to identify the following patterns.
In the first group, the content of retinol within the standard values, was detected in 73 patients (72.5%); values below the standard values were found in 28 examined women with uterine fibroids (27.5%).
In the second group of patients, retinol concentrations within the standard values were detected in 171 patients (59%); values below the standard values were found in 119 examined women (41%).
When testing the -tocopherol concentrations in the control group, its mean content was determined to be 1.23 mg%, the
lower and upper limits of the standard values for the specified fat-soluble vitamin were 0.88 and 1.74 mg%, respectively.
In the group diagnosed with uterine fibroids, the "average" concentration of the tested antioxidant was 0.82 mg%, the values o f the de te rmine d indic ato r we re significantly (p<0.05) lower by 33.3% of the "average" standard values.
In the group of patients with uterine cancer, the mean content of -tocopherol was 0.85 mg%, which was significantly (p<0.05) lower by 30.9% than the mean values of standard indicators.
The results obtained are presented in table 3.
Groups a- tocopherol (mg %)
Control (n=45) 1,23 ± 0,045
Myoma of the uterine body (n=101) 0,82 ± 0,039*
Cancer of the uterine body (n=290) 0,85 ± 0,052*
Note: * - p < 0.05 in relation to the control group
Table 3. The content of a-tocopherol in the blood serum of patients with myoma and cancer of the uterine body in comparison with the standard values (M±m)
An individual analysis of the data obtained made it possible to identify the following patterns.
In the first group, the content of -tocopherol within the limits of standard values, was detected in 53 patients (52%); values below the limit of standard values were found in 48 examined women with uterine fibroids (48%).
In the second group of patients, the concentrations of -tocopherol within the limits of standard values, were detected in 154 patients (53%); values below the limit of standard values were found in 136 examined women (47%).
Discussion of the results.
Taking into account the fact that the content of fat-soluble vitamins in the blood can reflect the state of the antioxidant status at the level of the whole organism [20], then, based on the results obtained, we can assume the presence of depression on the part of the LPO regulatory mechanisms in patients with
uterine tumors.
Currently, this condition is often associated with changes in micronutrient homeostasis and the development of nutrient imbalance, which can play an important role in the pathogenetic mechanisms of tumor growth in the human body [33].
When conducting a comparative analysis based on the principles of the Standards of Clinical Nutrition [10] and distinguishing five statuses of vitamin adequacy (deficient, marginal, normal, excessive and toxic), it was found that the percentage of individuals with deficiency and latent deficiency (marginal status) of -tocopherol (< 0.7 mg% ) and retinol (< 40 ) among patients with uterine myoma was 38.1% in the first case, 27.2% in the second, and among patients with uterine body cancer 28.3% and 41.4% respectively. While in practically healthy women, these values varied from 9% to 16% (Figures 1, 2, 3 and 4).
< 0,7 \
Mr% \
38% \
\ > 0,7
\ Mr%
\ 62%
Figure 1 - Percent distribution of a-tocopherol depending on the content in blood serum
in patients with uterine myoma
Figure 2 - Percentage distribution of retinol depending on the content in blood serum in
patients with uterine myoma.
Figure 3 - Percent distribution of a-tocopherol depending on the content in blood serum
in patients with uterine body cancer.
Figure 4 - Percentage distribution of retinol depending on the content in blood serum in
patients with uterine body cancer.
Thus, a distinctive feature of malignant tumor growth in uterus is a significant decrease in the levels of P-carotene, retinol and a-tocopherol in the blood. The results obtained indicate a directly proportional dependence of the decrease in the adequacy of fat-soluble antioxidant vitamins in patients with tumor diseases of the uterus. But at the same time, it should be noted that if in patients with myoma in the blood the deficiency of tocopherol is more pronounced, then in patients with uterine body cancer there is a predominance of retinol deficiency.
At the present, it has been established that such fundamental processes as cell differentiation and apoptosis are retinol-associated [1, 26]. It has been shown that retinoic acid acts as a ligand for nuclear receptors, which play the role of transcription factors that control gene expression and, as a consequence, the activity of proliferative processes. Cross coupling with a number of transcription factors, especially with AP1, explains the antitumor effect of retinoids [15]. Therefore, their low level in the body is a risk factor for carcinogenesis.
It sho uld be emphasized that antioxidant defense has a multicomponent organizational structure aimed at maintaining a closed loop in regulation of free radical reactions according to the principle of negative feedback. Violation of the dynamic balance between the level of antioxidant protection and the activity of radical processes can become an important pathogenetic link in oncogenesis in the body, including tumor diseases of the uterine body.
Conclusion. The results obtained indicate that in uterine cancer, in contrast to uterine body fibroids, a more pronounced inhibition of the antioxidant system activity
is determined, which is manifested in a significant decrease in the levels of -carotene, retinol and a-tocopherol in the blood, which have the ability not only to inhibit lipid peroxidation, but also to induce immunological activity and inhibit the growth of tumor cells, the significance of which in the mechanisms of development of tumor growth is beyond doubt.
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