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Berstein L.M.,Nnpetrov Research Institute Of Oncology
Voprosy Onkologii | Year: 2016

An inflammation expressed in a moderate degree and having a chronic character is associated with the local changes in the tumor and adipose tissue (manifested, in particular, by lymphocytic and macrophage infiltration) as well as with systemic shifts involving hormone and hormone-like elements for their implementation. The unfavorable consequences of these shifts may be restrained due to the endogenous anti-inflammatory reserves (systems) and intentionally used exogenous agents with the same action. These issues are considered on the example of endometrial cancer, for the occurrence and course of which a considerable significance is attributed to the excess of body fat, especially in its "standard", rather than "metabolically healthy" variant. The importance of analysis of discussed factors is additionally enhanced due to the changes in understanding of the nature of endometrial cancer and contemporary breakaway from the dualistic principle of its division into separate types.

Tsyrlina E.V.,Nnpetrov Research Institute Of Oncology
Voprosy Onkologii | Year: 2016

There is considered one of the side effects of tamoxifen - the formation of ovarian cysts associated by also excessive production of estradiol. Data on likely mechanism of development of hyperestrogenia and its possible influence on anti-tumor effect of tamoxifen are presented.

Berstein L.M.,Nnpetrov Research Institute Of Oncology | Yue W.,University of Virginia | Wang J.-P.,University of Virginia | Santen R.J.,University of Virginia
Breast Cancer Research and Treatment | Year: 2011

Resistance to tamoxifen (TAM) and aromatase inhibitors represents a major drawback to the treatment of hormone-dependent breast cancer, and strategies to overcome this problem are urgently needed. The anti-diabetic biguanide metformin (MF) exerts pleiotropic effects which could enhance the effectiveness of available hormonal therapies. This study modeled several aspects of hormonal therapy in women and examined the effectiveness of MF under those conditions. For cell growth evaluation, wild-type (wt), TAM-resistant (TAM-R), and long-term estradiol-deprived (LTED) MCF-7 cells, as a model of aromatase inhibitor resistance, were grown in the presence or absence of TAM or MF for 5 days. For immunoblot analysis and aromatase activity measurements, these cells were grown for 48 h. Wild-type and LTED cells were equally sensitive to the growth inhibitory effects of TAM and MF, while TAM-R cells were less sensitive to TAM than to MF. Partial additive effects on cell number of TAM combined with MF were greatest (if compared with isolated TAM action) in TAM-R and LTED cells. In contrast to the decrease in PCNA values in TAM-resistant cells treated with the TAM and MF combination, no other changes were found in the levels of this proliferation marker. These findings suggested a major component of apoptosis in the growth inhibitory effect. This was confirmed with Western blot analysis of PARP and caspase 7 as well as with apoptosis ELISA assay. MF also altered signaling pathways. AMP-kinase was stimulated by MF approximately equally in MCF-7, TAM-R, and LTED cells, while inhibition by biguanide of p-S6K as a downstream target of mTOR was strongest in TAM-R cells. Under the influence of MF, expression of ER-α was decreased in wt MCF-7 cells suggesting possible involvement of this compound in estrogen signaling. Metformin interacts additively with TAM to reduce neoplastic cells growth. The cellular context (including loss of sensitivity to TAM and estrogen deprivation) is of importance in influencing breast cancer responses to MF and to a combination of MF and TAM. © 2010 Springer Science+Business Media, LLC.

Anisimov V.N.,Nnpetrov Research Institute Of Oncology
Oncotarget | Year: 2015

During the last decade, the burst of interest is observed to antidiabetic biguanide metformin as candidate drug for cancer chemoprevention. The analysis of the available data have shown that the efficacy of cancer preventive effect of metformin (MF) and another biguanides, buformin (BF) and phenformin (PF), has been studied in relation to total tumor incidence and to 17 target organs, in 21 various strains of mice, 4 strains of rats and 1 strain of hamsters (inbred, outbred, transgenic, mutant), spontaneous (non- exposed to any carcinogenic agent) or induced by 16 chemical carcinogens of different classes (polycycIic aromatic hydrocarbons, nitroso compounds, estrogen, etc.), direct or indirect (need metabolic transformation into proximal carcinogen), by total body X-rays and γ-irradiation, viruses, genetic modifications or special high fat diet, using one stage and two-stage protocols of carcinogenesis, 5 routes of the administration of antidiabetic biguanides (oral gavage, intraperitoneal or subcutaneous injections, with drinking water or with diet) in a wide ranks of doses and treatment regimens. In the majority of cases (86%) the treatment with biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed. Very important that there was no any case of stimulation of carcinogenesis by antidiabetic biguanides. It was conclude that there is sufficient experimental evidence of anti-carcinogenic effect of antidiabetic biguanides.

Berstein L.M.,Nnpetrov Research Institute Of Oncology
Future Oncology | Year: 2010

Comparing the experience accumulated for more than 40 years in the Laboratory of Endocrinology of Petrov Institute of Oncology (St Petersburg, Russia) with similar approaches practiced elsewhere, evidence supports the reasonability of metabolic rehabilitation of patients suffering from breast cancer or other hormone-dependent malignancies. The primary objective of such approaches is to improve treatment results by ameliorating hormonal-metabolic disturbances, including excess body fat, glucose intolerance, insulin resistance and manifestations of endocrine-genotoxic switchings, and modify tissue and cellular targets or mechanisms related or nondirectly related to the aforementioned disturbances. The relevant measures may be categorized as pharmacological (antidiabetic biguanides exemplified with metformin being most popular but not exclusive) and nonpharmacological (rational nutrition, moderate physical activity and so forth) and used separately or in different combinations. © 2010 Future Medicine Ltd.

Berstein L.M.,Nnpetrov Research Institute Of Oncology | Iyevleva A.G.,Nnpetrov Research Institute Of Oncology | Vasilyev D.,Nnpetrov Research Institute Of Oncology | Poroshina T.E.,Nnpetrov Research Institute Of Oncology | Imyanitov E.N.,Nnpetrov Research Institute Of Oncology
Cell Cycle | Year: 2013

Metformin is a well-known antidiabetic medication, which, besides diabetes, may be involved into modulation of other age-related pathologies, including cancer. The study concerns 12 gene polymorphisms divided into 2 groups consisting of 6 genes each. The first group was composed from so-called "standard" (S) polymorphisms, for which the connection with metabolic response to metformin is already established. The second group included polymorphisms of genes encoding proteins possibly connected with diabetes mellitus type 2 (DM2), impaired glucose tolerance or cancer and entitled here as "associated" (A). A total of 156 postmenopausal women (average age 60.7 ± 0.7) were included, 37 of them healthy, 64 with type DM2 and concurrent treatment-naïve cancer (mostly breast, endometrial or colorectal cancer), 32 with DM2 without cancer, and 23 with treatment-naïve cancer and normal glucose tolerance. The leading metformin response S-marker in combined group of DM2 patients was the CC variant of OCT1-R61C polymorphism of organic cation transporter protein 1 gene. In cancer patients without DM2, this position belonged to AC and AA genotypes of OCT1-rs622342 polymorphism. Among the A-polymorphisms, GA variant of sex hormone-binding globulin gene SHBG-D356N was less frequently observed in DM2 patients with or without cancer. Besides, in diabetics, the same polymorphic variant of SHBG as well as GC genotype of oxidized lipoprotein receptor OLR1-G501C and GG genotype of locus rs11065987 near BRAP gene were carried rather often in combination with "metformin-positive" variant of OCT1-R61C. In addition, carriers of OCT1-R61C and OCT1-rs622342 polymorphisms with potentially positive reaction to metformin had higher insulin resistance score (HOMA-IR) values. Received data lead to the conclusion that postmenopausal diabetics, both with and without cancer, differ in genetic stigmata of potential response to metformin less than they differ from cancer patients without DM2. As genetic polymorphisms associated with metabolic and anticancer metformin (and, possibly, phenformin) effects may be different, this subject requires further investigation. © 2013 Landes Bioscience.

Semiglazov V.F.,Nnpetrov Research Institute Of Oncology
Voprosy Onkologii | Year: 2016

This manuscript includes an update on the latest developments in the biology of breast cancer as well as the most recent advances in prevention and multidisciplinary management of this disease: surgery after neoadjuvant chemotherapy and anti-HER2 therapy of HER2 positive breast cancer, neoadjuvant and adjuvant endocrine treatment of ER+ (Luminal A) breast cancer. Our task (as in the St. Gallen and ESMO consensus recommendations) is to assist physicians to improve both therapy impact in patients and their results.

Imyanitov E.N.,Nnpetrov Research Institute Of Oncology
Voprosy Onkologii | Year: 2016

Until recently the detection of carriers of mutations in hereditary cancer genes was aimed almost exclusively to the detection of subjects-at-risk, and consequently, personalized monitoring and preventive actions. However, it was revealed several years ago that some hereditary cancers are characterized by unique biological features and, therefore, unusual spectrum of drug sensitivity. For example, BRCAl/2-associated cancers usually demonstrate somatic loss of the remaining gene allele, and, hence, tumor-specific defects of DNA repair of double-strand breaks. This mechanism determines increased sensitivity of BRCAl/2-related cancers to cisplatin, mitomycin C and PARP inhibitors. Cancers arising as a part of Lynch syndrome can be effectively treated by the modulators of immune response. Tumors in patients with tuberous sclerosis often regress after administration of mTOR inhibitors. For the time being, there is already about a dozen of drugs demonstrating specific activity towards certain categories of hereditary cancers.

Berstein L.M.,Nnpetrov Research Institute Of Oncology
Aging | Year: 2012

Metformin, an oral anti-diabetic drug, is being considered increasingly for treatment and prevention of cancer, obesity as well as for the extension of healthy lifespan. Gradually accumulating discrepancies about its effect on cancer and obesity can be explained by the shortage of randomized clinical trials, differences between control groups (reference points), gender-and age-associated effects and pharmacogenetic factors. Studies of the potential antiaging effects of antidiabetic biguanides, such as metformin, are still experimental for obvious reasons and their results are currently ambiguous. Here we discuss whether the discrepancies in different studies are merely methodological or inherently related to individual differences in responsiveness to the drug. © Berstein.

Pliss G.B.,Nnpetrov Research Institute Of Oncology
Voprosy Onkologii | Year: 2016

In December, 2016 it will be 140 years since the birth of N. N. Petrov-the outstanding figure of native oncology' who laid the foundation of the new practical and scientific direction of works in the USSR in the XX century executed.

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