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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. Source

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. Source

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. Source

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. Source

Merabishvili V.M.,Nnpetrov Research Institute Of Oncology
Voprosy Onkologii | Year: 2016

Malignant tumors of male breast are a rare phenomenon not only in Russia but also in other countries. Possibility to evaluate the incidence of these tumors among men appeared in Russia only since 2011. In Leningrad such data are published since 1980 and then they became a part of data on primary male patients with breast cancer in the IARC monographs "Cancer in 5 continents" from VI up to X volumes. This paper presents an analysis of the prevalence of breast cancer in men through the world and Russia. Detailed characteristics of data on patients according to digit 4 of ICD-10, the level of morphological verification along different age groups and the feature of histological structure of tumors has been conducted on database of the Population-based Cancer Registry of St. Petersburg. For the first time there are estimated relative survival rates in men diagnosed with breast cancer on the population level. Source

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