In endometrial hyperplasia the total proteasome activity was not changed however the 26S proteasome activity was increased in comparison with the normal tissues. In endometrial cancer the high total proteasome activity and activities of 26S and 20S proteasomes wer e revealed. The changes in proteasome activities were correlated with the decreased content of α1α2α3α5α6α7 proteasome subunits and increased con- tents of LMP2, LMP7 and PA28β proteasome subunits compared to that in nonaltered tissues. Low content of α1α2α3α5α6α7 proteasome subunits was revealed at the second stage of cancer patients in comparison with that at the first stage.

Objective: to study the urinary levels of estrogen metabolites as a diagnostic criterion in patients with cancer of the cervix uteri (CCU) associated with human papillomavirus (HPV) infection to provide a rationale for the use of pathogenetic therapy in the combination treatment of CCU.Subjects and methods. The study enrolled 26 patients with Stages I-IV CCU who were treated at the Department of Gynecology, Tomsk Research Institute of Oncology. The patients’ mean age was 45.6±1.3 years (range 24 to 72 years), the patients of reproductive age ac- counted for 50%. Tumor was staged in accordance with the FIGO classification. Genotyping was carried out on 12 oncotropic types, by estimating the viral load by polymerase chain reaction. Urinary estrogen metabolite levels were measured in all patients.Results. In the female patients, the urinary level of the metabolite 2-OHE1 responsible for normal cell growth was 8.95±2.9 ng/mg, which was significantly below the values in healthy women (19.7±1.2 ng/mg). The level of the metabolite 16

Insulin-like growth factors (IGFs) and the nuclear factor κB (NF-κB) are known to play an important role in pathogenesis of endometrial cancer. However, there is still uncertainty about their proteolytic regulation. We studied the correlation between chymotrypsin-like activity of proteasomes and IGF-I, IGF-II, and NF-κB levels in endometrial cancer tissues. The total activity of proteasomes and the 20S and 26S proteasome activities were shown to be significantly higher in malignant tumors than in the unaltered endometrium. Negative correlations were found between the proteasome activity of 26S and the p50 level of NF-κB, as well as between the 26S and 20S proteasome activities and IGF-I level. The obtained data indicate the possible proteasome regulation of growth and transcription factors. As the major pool of IGF-I is considered to be located in the extracellular space, it is likely that extracellular proteasomes also take part in the regulation of the IGF-I content. The positive correlation between the IGF-I level and PAPP-A metalloproteinase is evidence that this proteolytic enzyme is another important regulator of the level of growth factor, which ensures the proteolysis of IGF-I binding proteins and, thus, increases the concentration of IGF-I in tissues. The present data show the possibility of the proteolytic regulation of growth and nuclear factors that can play an important role in cancer pathogenesis.

Инсулиноподобные факторы роста (ИФР) и ядерный фактор B (NF- B) играют важную роль в патогенезе рака эндометрия, однако их протеолитичекая регуляция не изучена. В представленной работе анализировали связь между химотрипсиноподобной активностью протеасом и содержанием ИФР-I, ИФР-II и NF- B в тканях рака эндометрия. Показано, что суммарная активность протеасом и пулов 20S и 26S протеасом в злокачественных опухолях значительно выше, чем в неизмененном эндометрии. Обнаружены отрицательные корреляционные связи между активностью пула 26S протеасом и содержанием р50 NF- B, а также между активностью пулов 26S и 20S протеасом и содержанием ИФР-I. Полученные данные свидетельствуют о возможной регуляции содержания ростового и транскрипционного факторов протеасомами. Считается, что ИФР-I находится преимущественно во внеклеточном пространстве, поэтому в регуляции содержания ИФР-I, вероятно, принимают участие и внеклеточные протеасомы. Существование положительной корреляции между уровнями ИФР-I и металлопротеиназы PAPP-A дает основание считать, что этот протеолитический фермент можно рассматривать как важный регулятор содержания фактора роста, который расщепляет белки, связывающие ИФР-I, и тем самым повышает его уровень в тканях. Показана возможность протеолитической регуляции ростовых и ядерных факторов, что может играть важную роль в патогенезе злокачественных новообразований.

Objective: to study the urinary levels of estrogen metabolites as a diagnostic criterion in patients with cancer of the cervix uteri (CCU) associated with human papillomavirus (HPV) infection to provide a rationale for the use of pathogenetic therapy in the combination treatment of CCU. Subjects and methods. The study enrolled 26 patients with Stages I-IV CCU who were treated at the Department of Gynecology, Tomsk Research Institute of Oncology. The patients mean age was 45.6±1.3 years (range 24 to 72 years), the patients of reproductive age accounted for 50%. Tumor was staged in accordance with the FIGO classification. Genotyping was carried out on 12 oncotropic types, by estimating the viral load by polymerase chain reaction. Urinary estrogen metabolite levels were measured in all patients. Results. In the female patients, the urinary level of the metabolite 2-OHE1 responsible for normal cell growth was 8.95±2.9 ng/mg, which was significantly below the values in healthy women (19.7±1.2 ng/mg). The level of the metabolite 16α-OHE1 playing a key role in tumor cell transformation was 14.95±4.4 ng/mg, which did not differ significantly from the level in healthy women (15.2±2.4 ng/mg). There were no statistically significant differences in the levels of estrogen metabolites depending on tumor differentiation; but there was an inversely proportional relation to the stage of the process. Conclusion. The change in the estrogen metabolite ratio of 2-OHE1/16α-OHE1 toward a preponderance of the aggressive metabolite 16α-OHE1 contributes to the induction of the mechanisms of estrogen-dependent carcinogenesis. In this connection, it is expedient to use etiopathogenetic agents to block the key mechanisms of carcinogenesis in the combination treatment of CCU.

Hormonal and energetic status was studied in 138 patients with endometrial hyperplasia and endometrial cancer. The comparative analysis of hormonal status (LH, FSH, estrogen, progesterone, testosterone, prolactin, SHBG), energetic status (leptin, grelin, insulin) and the assessment of lipid and carbohydrate metabolisms were carried out for patients with proliferative processes in the endometrium with the evidence of metabolic syndrome and without it. The study showed that the changes in hormonal status were characterized by a high frequency of disturbances with development of hyperestrogenemia (72 %), hypertestosteronemia (65 %), hyperinsulinemia (81 %) and hyperleptinemia (68 %). Moreover, the LH level and LH/FSH index were increased and FSH and progerterone levels were decreased. Significant changes in both carbohydrate (hyperinsulinemia, insulin resistance) and lipid (hypercholesterolemia, hypertriglyceridemia) metabolisms were revealed. Mechanisms of hormonal correlations which uderlie pathological endometrial process were suggested. Further investigations are required to individually prognosticate endometrial cancer process and to form the groups at high risk for endometrial cancer based on the assessment of hormonal and energetic balances, as well as to correct properly metabolic disorders in patients with endometrial hyperplasia and endometrial cancer.

New data on a high expression of insulin-like growth factor -I (IGF-I) and IGF-binding protein-3 (IGFBP-3) in endometrial tumors as compared to endometrial hyperplasia samples have been presented. A significant variability in the expression of specific IGFBPs proteinase (PAPP-A) in endometrial tumors was found. The reduction in the PAPP-A level with high level of IGBP-3 in low-differentiated carcinomas was observed. The level of IGF-I in non-invasive endometrial cancer was significantly lower then that in invasive cancer. The relationship between proteasome activity in non-transformed tissue and IGF-I level in the endometrial tumors was revealed. The levels of IGFBP-3 and proteasome activity were related with the age and menopausal status and the level of IGFBP-3 was related with hypertension in endometrial cancer patients.

The review presents the modern concept on the relationship between metabolic syndrome and endometrial cancer. Metabolic syndrome is one of the main risk factors for cardio-vascular diseases, carbohydrate metabolism injury and reproductive system pathology. The incidence of endometrial cancer is 2-3 times more frequent with the evidence of metabolic syndrome. It is caused by aggravation of insulinoresistance, increase in androgen production by ovaries, and formation of stable anovulation resulting in progression of pathological changes in the endometrium and accumulation of carbohydrate metabolic products with anti-proliferative action. The role of obesity as a risk factor for development of uterine body cancer is more significant in reproductive age than in menopause.