[Effectiveness of aromatase inhibitors in comparison with metformin for neoadjuvant treatment in patients with endometrial cancer].

We compared the efficacy of endometrial cancer neoadjuvant treatment in 38 patients receiving nonsteroid (letrozol, anastrozol) or steroid (ekzemestan) aromatase inhibitors and 12 patients receiving metformin. The changes in glucose metabolism were revealed in 26.3% of patients treated with aromatase inhibitors and 16.7% of patients treated with metformin. However, comparison of endometrial thickness (M-echo signal) data, postoperative data on favorable differentiation grade changes rate and proliferative activity (Ki-67 expression) revealed the superiority of 2-4 weeks aromatase inhibitors course in comparison with 2-9 (average 5.3 +/- 0.7) weeks metformin treatment.

[Influence of metformin and N-acetylcysteine on hormonal and genotoxic effects of estrogens and glucose in convalescent cancer patients].

Our study involved 25 postmenopausal patients (endometrial carcinoma--16, breast (6) and colorectal (3) cancer, aged 56.8 +/- 0.9). All patients were in clinical remission. None had received any specific therapy for at least 12 months. After a laboratory endocrine-genotoxic switch evaluation, 17 patients were given an antidiabetic drug--biguanide metformin--or N-acetylcysteine as antioxidant (8) for 3 months. A checkup was carried out on completion of the course. As a result, hormonal and progenotoxic effects of glucose were found to be inhibited significantly. Much less pronounced was the impact on relevant effects of estradiol which were investigated vis-a-vis nature of blood mononuclear response in vitro. Both isolated and combined administration of said drugs used for endocrine-metabolic rehabilitation is justified.

[Diabetes mellitus and obesity: projection onto oncological morbidity].

Peculiar features of human morbidity and their changes in time are registered chronologically starting from the XVII-VYIIIth centuries. After the period of predominantly infectious diseases, chronic and non-communicable conditions continued to gain momentum in the last 3-5 decades. Side by side with AIDS, accidents, effects of smoking etc, the global epidemics of diabetes mellitus and obesity comes up to take a leading place in the general population morbidity. In this communication, possible causes of this situation and its possible association with cancer are considered based on the results of original studies. Measures for the prevention and treatment of these diseases are discussed.

[Criteria for evaluating the effectiveness of aromatase inhibitors in the neoadjuvant treatment of patients with endometrial carcinoma].

Clinical and experimental effects of neoadjuvant treatment of endometrial cancer patients with non-steroidal aromatase inhibitors: letrozole (femara, n=10, 2.5 mg/day, 14 days), anastrozole (arimidex, n=15,1 mg/day, 28 days) and exemestane (aromazine, n=13, 25 mg/day, 14 days) were compared. Administration of anastrozole was mostly frequently followed by pain relief in the lower abdomen and/or decreased rates of uterine discharge. Endometrial wall thickness (M-echo signal) decreased significantly in 60% of patients receiving anastrozole, exemestane - 58.3% and letrozole - 40%. Substantial drop in intratumoral aromatase and blood estradiol levels occurred more frequently after anastrozole and letrozole while progesterone receptor levels in tumor were markedly lower after exemestane administration. Assay of blood LH (except letrozole), FSH and cholesterol appeared to be of less relevance. On the contrary, significance of assessment of marker Ki-67 expression, which, in the case of anastrozole, dropped in 6 out of 12 patients after a 28-day course, could hardly be underestimated.

[An immunohistochemical study of aromatase, estrogen 4-hydroxylase and fatty acid synthetase in breast cancer tissues from BRCA1 mutation carriers].

Breast cancer in germline BRCA1 mutation carriers features a peculiar endocrine and metabolic profile which is yet to be studied properly in clinical settings. We used a novel immunohistochemical method to compare expression levels of aromatase, estrogen 4-hydroxylase (CYP1B1) and fatty acid synthetase in breast cancer tissues from 12 BRCA1 mutation carriers and 22 non-carriers. Rates of aromatase in carriers were significantly higher than in control (p=0.04) to match the data obtained earlier in cell lines employed in down-regulation of the wild BRCA1 gene. These findings make a case for use of aromatase inhibitors in such patients. No differences in CYP1B1 and fatty acid synthetase expression levels were found between the mutation and the wild BRCA1 gene groups. Further search is warranted for manifestations of excess genotoxic effects of estrogens and enhanced lipogenesis in BRCA1 mutation carriers.

[Progenotoxic shift in mammary adipose tissue (adipogenotoxicosis): association with clinical and biological characteristics of breast cancer].

The study is concerned with identification of a relationship between levels of production and accumulation of compounds capable of hormonal and progenotoxic effects in mammary fat, on the one hand, and characteristics of tumor tissue in breast cancer, on the other. Mammary fat was sampled at a distance of 1.5-2 cm from tumor edge (79 pts.). Case histories were used to provide data on clinical stage, size, grade and regional lymph node involvement. Levels were assayed of leptin, adiponectin, tumor necrosis factor (TNF-alpha), interleukin-6 (IL-6), nitric oxide (NO), thiobarbiturate-reactive products (TBRP) and DNA oxidative damage marker (8-OH-dG) from 4hr-incubates of fat tissue culture. Mammary fat aromatase was assayed by radiometrical means while macrophage-assisted fat infiltration (CD68) and estrogen-4-hydroxylase (CYP1B1) expression were evaluated immunohistochemically. Radio-competitive and immunohistochemical methods were used to assay estrogen (ER) and progesterone (PR) receptor levels in tumor and tumor-related expression of cytokeratins 5/6 ("basal") and 7/8 ("luminal" epithelium), respectively. As far as hormonal properties of mammary fat were concerned, there were direct correlations between aromatase concentration, on the one hand, and tumor stage and size, on the other, and adiponectin secretion and CK7 expression in tumor. Besides, an inverse correlation was found between mammary fat-mediated release of leptin and adiponectin, on the one hand, and stage and regional lymph node involvement, on the other. The following main relationships were identified by comparison of the clinico-biological characteristics of tumor and markers of proinflammatory/progenotoxic properties of mammary adipose tissue: tendency toward direct correlation with IL-6 and 8-OH-dG in fat (tumor progress stage); direct correlation with TNF-alpha secretion rate (malignancy grade); lymph node involvement--tendency toward direct correlation with NO generation; CK5 expression in tumor--tendency toward direct correlation with 8-OH-dG, TBRP and CD68 fat infiltration; CK7 expression in tumor--tendency toward inverse correlation with NO generation in adipose tissue; ER-negative phenotype of tumor--tendency toward higher generation of TBRP, NO and TNF/leptin in fat. Hence, shift toward predominance of proinflammatory/progenotoxic properties of mammary adipose tissue (adipogenotoxicosis) is associated with signs of less favorable course of tumor process in the mammary gland which calls for working out adequate measures.

[Endocrine-genotoxic switchings as promoter of main noninfectious diseases].

Peculiarities of the incidence and spread of main non-infectious diseases (MNID) are in one or another way connected with the conception of "normal" and "successful" aging. The age-related increase in the frequency of MNID, associated with estrogen deficiency or excess, can be explained by the presence of estrogen effect switching phenomenon. The increase in the genotoxic effect of estrogens, isolated or combined with the weakening of the hormonal effect, can worsen the clinical course of MNID (including malignant tumors of hormone-dependent tissues). The effects of two other endocrine-genotoxic switchings (the joker function of glucose and adipogenotoxicosis) may realize in the same direction. The three mentioned phenomena form the so called basic triad, separate elements of which can interact. Endocrine-genotoxic switchings and their inductors are targets for prophylactic measures and, possibly, therapeutic ones. Both approaches may be divided into several groups with different points of application, whereas their ultimate goal is optimal balance between hormonal and DNA-damaging effects of estrogens, glucose, and adipose tissue-associated factors.

[Properties of mammary fat in breast cancer patients: topographic, systemic and environmental factors].

Breast cancer course may be influenced by a profile of steroids and peptides produced by mammary fat. The study was concerned with assessment of hormonal (leptin and adiponectin production, adipocyte diameter and aromatase level) and progenotoxic factors which characterize DNA damage (8-OHdG) and such cancer promoters as tumor necrosis (TNF-alpha), interleukin-6 (IL-6), nitric oxide (NO), thiobarbiturate reactive products (TRP), macrophage/histiocyte infiltration, estrogen 4-hydroxylase expression (CYP1B1) in mammary fat located 1.5-2 cm or not less than 5 cm away from tumor edge. Thirty-three pairs of mammary fat samples from 23 menopausal and 10 cycling patients were used. Closer proximity of mammary fat involved intensified biosynthesis of estrogens (as shown by aromatase level) and their conversion to catechol derivatives (as shown by CYP1B1 concentration) as well as accumulation of 8-OH-dG. Smoking and hyperglycemic patients and those with considerable mammary fat volume revealed accumulations of anti-inflammatory and progenotoxic cytokines (IL-6 or TNF-alpha). Hence, hormonal/progenotoxic ratio in mammary fat can be identified both by topographic, systemic and environmental factors.

[Registry-based analysis of cancer and diabetes combination: prevalence and features].

Neoplasia was established in 5.4% out of 15,813 patients with diabetes mellitus registered at the City Population-Based Cancer Register and Territorial Diabetic Center, St. Petersburg. Gender-unrelated decreasing order of tumor sites was as follows: breast, skin, uterus, colon and stomach. Broncho-pulmonary and gastric cancer incidence in male patients with diabetes was higher than in females (3.5 and 2.2 times, respectively). The relationship was reversed with thyroid cancer and skin melanoma (4.4 and 2.3 times, respectively). In patients with type 1 diabetes mellitus (10.3%), the cancer incidence pattern differed significantly from that in the whole diabetes-associated cohort of cancer patients: the former tended to involve such sites as pancreas, urinary bladder, stomach, cervix uteri, lung and skin. Data on age at diagnosis of cancer or diabetes, insulin therapy intensity and body mass were evaluated. The value of timely screening for both cancer and diabetes mellitus in such cohorts was confirmed.

[Hormonal and progenotoxic properties of mammary fat in pre- and postmenopausal cancer patients].

Since breast cancer may emerge both before and after menopause onset, relevant forms of the disease show marked biological and clinical differences. Intrinsic properties of mammary fat located in the vicinity of tumor, which play a definitive role in stromal-epithelial interactions, are an important factor of development of such differences. The DNA damage promoting hormonal (leptin and adiponectin production, aromatase activity) and progenotoxic. The properties of mammary fat such as formation of tumor necrosis factor, interleukin-6, nitric oxide, malonic aldehyde, macrophage/histiocyte infiltration and estrogen 4-hydroxylase expression, were studied in mammary fat tissue of 95 patients with receptor-positive or receptor-negative breast tumors (reproductive--25, menopausal--70). It was found that progenotoxic properties might somewhat predominate, as far as differences in parameters and pathways are concerned, both in menopausal and still cycling patients. Hence, progenotoxic damage which represents mammary fat tissue status is perhaps modified by a number of genetic and mitochondrial factors. It may exert unfavorable effect on the course of the disease within a fairly wide period.

[Comparison of letrozole and exemestane used in non-adjuvant therapy of endometrial carcinoma].

The clinical and endocrine-related effects of 2-week preoperative treatment of endometrial carcinoma patients with a non-steroid inhibitor of letrozole aromatase (femara 2.5 mg/day, n=10) and a steroid inactivator of the enzyme (exemestane 25 mg/day, n=13) were compared. In the first group, pain relief in the lower part of the belly and/or decreased uterine discharge were reported in two cases, as well as a 31% drop in the mean endometrial M-echo (ultrasound) signal. In the exemestane group, two patients revealed moderate uterine discharge decrease matched by a 15.6% decrease in M-signal intensity; no tumor was detected in another patient on completion of the course. Letrozole effect was relatively greater when such parameters as tumor-tissue aromatase level, estrogen concentration in vaginal smear and blood-cholesterol, FSH and LH levels were taken into consideration. However, exemestane therapy involved a relatively sharper drop in the levels of tumor receptors of progesterone and a significantly higher estrogen/progesterone receptor ratio. Hence, no matter how short treatment duration was, both steroid and non-steroid aromatase inhibitors induced effects predominantly associated with lowering estrogen production in endometrial carcinoma patients. This makes a case for further clinical trials of these drugs to deal with the pathology.

[Genetic polymorphism of steroidogenic enzymes and steroid receptor level in tumors of the reproductive system]. / Geneticheskii polimorfizm fermentov steroidogeneza i soderzhanie retseptorov v opukholiakh reproduktivnoi sistemy.

The strategy of therapy and prognosis of reproductive system neoplasia generally depend on the steroid receptor status of tumor. The causes of formation of steroid receptor-free tumors are to be investigated. The genetic polymorphism of CYP19 (aromatase), CYP17 (17-hydroxylase; 17,20-lyase), CYP1B1 (4-estrogen hydroxylase) and COMT (catechol-O-methyl transferase) was studied in a total of 254 patients with breast and endometrial cancer, with particular reference to the association of certain polymorphisms and receptor status of tumor. It was found that the lack of estrogen receptor (ER) in breast tumor was due to a deficit in the A3A6 allele (p(0.01), while the absence of progesterone receptors was associated with a lower incidence of the A1A1 and A1A2 variants (p = 0.022) of tetranucleotide repeats in the CYP19 gene. In the same patients, receptor-negative tumors occurred more often (p = 0.032) than in combinations of higher level of 4-hydroxylase estradiol of S-allele in position 48 (Gly/Arg) of the CYP1B1 gene. Moreover, endometrial carcinoma patients tended to reveal (p = 0.058) an increased ratio of A6A7-CYP19 to allele A1-containing variant. No other distinctions between R(+) and R(-) tumors were identified. It is suggested that peculiar polymorphisms of steroidogenic enzymes may moderately influence the genesis of R(-) neoplasms which may be associated with either the rate of estrogen biosynthesis or, as in the case of CYP1B1, with formation of genotoxic derivatives of estrogens. The latter point is to be investigated further.

[Tumor tissue aromatase and estrogen levels versus clinical course of endometrial cancer]. / Aktivnost' aromatazy, tkanevoe soderzhanie éstrogenov i osobennosti techeniia raka éndometriia.

Levels of aromatase, a key enzyme in estrogen biosynthesis, were assayed in tumor tissue sampled from 25 patients with endometrial cancer. In addition, estradiol concentrations were compared in normal and altered endometrial tissue from 78 patients suffering uterine cancer. Unlike breast cancer, aromatase was not detectable in altered endometrium unless tissue estrogens could be identified in both normal and tumor tissue. Hence, aromatase presence served as an indicator of malignant transformation. Its concentration in samples of uterine tissue varied 0-28.4 fM/mg protein/hr (an average of 12.9(1.7 fM/mg protein/hr). There was hardly any correlation between this level, on the one hand, and menopause and body mass, on the other. Yet, it tended to increase in step with stage of disease and cell differentiation decline. Estradiol concentrations in malignant endometrium in both reproductive and menopausal patients were higher than in macroscopically normal ones, while still cycling women tended to show higher values than menopausal ones. Although there was no significant difference in estradiol levels in the altered endomentrium of patients with pathogenetical patterns of uterine cancer stage I and II, they did show a direct correlation with clinical stage of tumor process and depth of invasion into the underlying myometrium. Hence, unlike estrogens circulating in blood, those contained in tissue ("intratumor") ones did enhance the aggressiveness of endometrial cancer course. It will be for further investigations to show whether it is due to an estrogen fraction being carried away by tumor from the circulation, or estrogens being synthesized by aromatase in tumor itself.

[Genetic polymorphism of steroid 17 alpha-hydroxylase/17,20-lyase (CYP17) and hyperinsulinemia in endometrial carcinoma]. / Polymorfism gena steroid-17-al'fa-gidroksilazy/17,20-liazy (CYP17) i giperinsulinemiia pri rake tela matki.

Initiation and/or promotion of endometrial carcinoma is considered to be associated with estrogens and androgens (androstendione) excess as well as hyperinsulinemia and resistance to insulin. It is possible that certain polymorphisms of the genes involved in steroidogenesis or steroid metabolism contribute to carcinoma susceptibility. In the current study, we compared the role of CYP17 biallelic MspA1) polymorphism in 114 endometrial carcinoma patients and 182 healthy women. According to our data, A2/A2 CYP17 genotype traditionally regarded as "unfavorable" was less frequent in cancer patients than in control which confirmed the results of two previous publications. For the first time, carriers of the genotype were shown to have relatively low levels of blood insulin and C-peptide. No significant difference was found between mean concentrations of testosterone, dehydroepiandrosterone sulfate and those of estradiol in the carriers of various CYP17 genotypes with endometrial cancer. Hence, CYP17 polymorphism which is represented by the "normal" A1/A1 genotype might be a factor of risk for endometrial carcinoma. Since this genetic variety may develop through an unconventional (nonsteroid) pathway, taking relevant preventive measures in high-risk groups should be recommended.

[Neoadjuvant use of the aromatase inhibitor letrozole in uterine cancer: endocrine and clinical effects]. / Neoad''iuvantnoe primenenie ingibitora aromatazy letrozola pri rake tela matki: éndokrinnye i klinicheskie éffekty.

Endometrial cancer (EC) is estrogen-dependent tumor in the hormonal treatment of which mostly progestins are used. During last 5-7 years feasibility of aromatase inhibitors use in EC is discussed without any special practical move in this direction. To evaluate possible biological response of tumor and patients to such treatment, we conducted a short pilot study involving 10 primary postmenopausal EC patients, mostly stage Ia,b (average age 59) who received letrozole (Femara, Novartis) 2.5 mg/day during 14 days before operation. Clinical, sonographical, morphological, cytological and hormonal-metabolic (blood estradiol, FSH, LH, glucose, lipid fractions by RIA or enzyme-colorimetric methods; tumor progesterone receptors by LBA and aromatase activity by 3H-water release assay) studies were included into the protocol before and after treatment. Tolerability of letrozole was satisfactory in all patients. 2 patients reported decrease of pain and pathological secretions from uterine cavity. In 3 patients, decrease in M-sonographical endometrial signal was registered; average value after treatment was 31.1% lower than before it. Tendency to the decrease in estrogenicity of vaginal smears was revealed. Average decrease in blood estradiol was 37.8% and in progesterone receptor level and aromatase activity 34.4% and 17.5% respectively. Decrease of aromatase activity in tumor tissue was registered mostly in normal weight patients. A more detailed and longer randomized study of aromatase inhibitors in EC performed in neoadjuvant setting deserves consideration.

[A polymorphism study of the CYP19 gene in endometrial cancer patients]. / Izuchenie polimorfizma gena CYP19 u bol'nykh rakom éndometriia.

A strong connection is known to exist between initiation/promotion of endometrial cancer and excess of estrogens. Therefore, participation of certain alleles of genetic polymorphisms in steroid biosynthesis or metabolism may be responsible for predisposition to the disease. The present study, comparing CYP19 (aromatase) gene polymorphism in 85 patients and 110 healthy females, pointed to a more frequent occurrence of relatively longer alleles (A6 and A7) of the CYP19 gene in the former group. Furthermore, precisely those genotypes co-occurred more frequently with elevated blood levels of estradiol and testosterone in postmenopausal patients. Hence, CYP19 gene polymorphism may be regarded as a factor of genetic risk for endometrial carcinoma.