P53 protein is considered to be the major tumor suppressor in human cells. Cancer cells do not survive if the p53-mediated signaling pathways function properly. However, about half of all malignancies still express wild type p53. One of the explanations to this is that p53 is suppressed by overexpression of p53-specific E3-ubiquitin ligases: Mdm2, MdmX, Pirh2 and Cop1. Pharmacological inhibition of protein-protein interactions between p53 and these negative regulators is a promising therapeutic approach to treat cancers retaining wild type p53. To date, a series of chemical inhibitors of p53 interactions with Mdm2 and MdmX E3-ubiquitin ligases have been discovered and characterized. Several of them are in the early stages of clinical trials. Despite this fact, their clinical efficacy may be hampered by a number of reasons, including tumor-specific expression of multiple isoforms of the target E3-ligases, which become inert to treatment with small molecules. This and other biochemical mechanisms of possible resistance of tumor cells with wild type p53 to small molecules against its negative regulators will be discussed in this review.

Chronic lymphocytic leukemia (CLL) in association with glomerulonephritis (GN) and renal failure is a serious problem in terms of therapy. The paper reports a clinical case of a 64-year-old female patient with Binet stage C CLL accompanied by minimal-change GN complicated by nephrotic syndrome and the development of acute renal failure. GN was diagnosed on the basis of electron microscopic studies of renal biopsy specimens. It was treated with rituximab in combination with bendamustine. The former was intravenously injected in a dose of 375 mg/m2 on day 0 of the cycle; the latter was given in a dose of 70 mg/m2 within the first 2 days; the cycle was repeated 28 days after initiation of the previous cycle. Five cycles could result in complete CLL remission (the follow-up duration was 20 months); nephrotic syndrome was completely abolished and kidney function recovered.

The paper describes a case of irreversible dilated cardiomyopathy in a young female patient receiving polychemotherapy for breast cancer.

Cytestrole acetate (CA), in the structure of which the steroidal antiestrogen component is associated with bis-β-cloroethylamino group, exhibits a strong cytotoxic activity against hormone-dependent cancer cell lines (CaOV, HeLa, MCF-7). In doxorubicin-resistant MCF-7 cells, CA potentiates the cytotoxic effect of etoposide and doxorubicin, and the IC50 for CA in these cells is 40 times lower than that for tamoxifen (TAM). In transplantable mice breast adenocarcinoma Ca-755, the therapeutic CA dose is 25 mg/kg when administered subcutaneously in oil solution for 5 days. On the DMBA-induced mammary tumors in rats, CA injected subcutaneously led to partial regressions 4 weeks after treatment in 75% of test rats, whereas TAM produced this effect in 43% of rats. Among various drug forms of CA, the most active were oil solution of CA in gelatin capsules for oral use and liposomal emulsion for intravenous administration, since these forms exhibited the highest values of Ca-755 tumor growth inhibition index (TGI = 97 - 98%).

Results of combined treatment, using roentgen-surgical interventions, of 58 patients, suffering noncolorectal metastatic affection of the liver, complicated in 20 (34.5%) of them by obturation jaundice, were analyzed. While resectability of the metastases, preoperatively chemotherapy (CHT) or chemoembolization of hepatic artery (CHEHA) in 1 - 2 courses were performed, and then - hepatic resection of various volume, adjuvant regional CHEHA or systemic CHT. Median survival of the patients have constituted 31.2 mo. While presence of nonresectable metastases a regional chemoinfusion via hepatic arteries or CHEHA (2 - 3 courses) were performed. Median survival of this group of patients have constituted 15.3 mo. Application of cytostatics for regional therapy have permitted in 4 (6.9%) patients, in whom partial tumor regression was achieved, to perform radical hepatic resection. Complete answer on the treatment was not achieved in any patient, partial answer was noted in 16 (33.3%), the process stabilization - in 20 (41.7%), the tumor progress - in 12 (25.0%). In total 170 endovascular and 41 transcutaneous transhepatic endobiliary interventions were performed. After operation 1 (12.5%) patient died.

Influenza is a respiratory infection widely spread around the world. Influenza complications are various in nature and in most cases involve the excessive proliferation of cells in respiratory tract as a factor of pathogenesis. In the present work the efficacy of the use of apoptosis inducer 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalenecarboxylic acid (AHPN) for prophylaxis of chronic damage on the stage of post- influenza pneumonia has been studied. Mice were infected with influenza virus A/mallard/Pennsylvania/10218/84(H5N2) with further study of the level of influenza virus reproduction in the lungs, specific mortality of animals and morphology of the foci of post-influenza pneumonia on the 15th day post inoculation. AHPN was shown to decrease the infectious activity of the virus in the lungs by 1.2-1.5 log10 EID50/0.2 mL depending on the dose as compared to the control group, in a weak decrease in mortality of animals (protection index was 12.5-37.5%). The application of AHPN restricted both the proliferative and infiltrative component in chronic post-influenza lesions. It demonstrated the most pronounced effect on the lung morphology when applied on days 4 to 7 post inoculation, i. e. in the period of maximal activation of inflammatory tissue infiltration and regeneration of bronchiolar epithelium. In conclusion, the use of apoptosis inducers can partially prevent the development of chronic post-influenza lesions with proliferative component.

In order to obtain new fundamental knowledge, patterns of manifestation of synergy have been studied after simultaneous combined action of hyperthermia (47.5-60 degrees C) with anti-tumor agents (cyclophosphamide, cisplatin) on the survival of yeast cells. To calculate the efficiency of the synergistic interaction, the dependence of cell survival on the duration of exposure at separate and simultaneous action of chemical agents and hyperthermia was used. We have found that there is a certain temperature range within which there is a synergistic enhancement of anticancer drugs and high temperature effects. Any deviation from the optimum values of the temperature results in a decrease in synergy. The possible mechanism of the revealed patterns is discussed.

The initial stages of in vitro differentiation of embryonic stem cells are considered as unique three-dimensional models of early development of mammals for basic, pharmacological, and toxicological studies. It has been previously shown (Gordeeva, 2012) that the assessment of embryotoxicity in the model of undifferentiated embryonic stem cells can be insufficiently accurate in predicting toxic effects on mammalian embryos. In view of this, we performed a comparative study of the damaging effects of the cytostatic etoposide in undifferentiated embryonic stem cells and embryoid bodiesof different stages of differentiation that have similar three-dimensional structures with early embryos. The analysis of growth, cell death, and dynamics of differentiation of embryonic stem cells and embryoid bodies exposed to etoposide showed that the cytostatic and cytotoxic effects of etoposide are stage-specific. The damaging effects of etoposide were maximum in the undifferentiated embryonic stem cells and decreased with growth and differentiation of embryoid bodies. We assume that the increase in the cell volume of embryoid bodies and the development of the hypertrophic we suggest that the increase of embryoid body volume and overgrowth of extraembryonic endoderm layer lead to a decrease in the diffusion, transport, and metabolism of chemical and bioactive substances and prevent the damaging effects.

The results of combined treatment in 82 patients for hepatic metastases of colorectal cancer, complicated in 14 (17.1%) of them by obturation jaundice, using roentgensurgical interventions, were analyzed. In case of resectable metastases, preoperative chemotherapy and chemoembolization of hepatic artery was conducted, using 1 - 2 courses of oxaliplatin, and further--hepatic resection in various volume (in 23 patients), adjuvant regional chemoembolization or systemic chemotherapy. Median survival of the patients in this group was 32.2 mo. While unresectable metastases presence (in 59 patients), the treatment with the help of regional chemoinfusion via hepatic artery or chemoembolization of hepatic artery (2 - 3 courses), using oxaliplatin or irinotecan, was conducted. Median survival of patients in this group was 16.7 mo. Application of oxaliplatin for treatment with the help of regional therapy have permitted in 8 (9.8%) patients, while partial efficiency of chemotherapy, to perform radical hepatic resection. Complete answer on therapy was noted in 6 (8.6%) patients, the partial--in 19 (27.1%), the state stabilization--in 37 (52.9%), the disease progress--in 8 (11.4%). In total in 82 patients there were performed 217 endovascular and 24 transcutaneous transhepatic endobiliary interventions. Postoperatively 5 (6.1%) patients died.

To interpret hematopoietic cell myelodysplastic changes found during the primary diagnosis of myelodysplastic syndromes or other diseases and during therapy is an enormously complex clinical and laboratory problem. In what cases do these changes serve as a manifestation of clonal disease and in what cases are these changes a result of various effects? Alimentary, toxic factors, infectious agents, and iatrogenic effects may cause myelodysplastic signs in the hematopoietic cells. This review depicts diverse hematopoietic cell dysplastic changes that can be observed as a result of the effects of one drug or another, toxic factors, and infectious agents.

To assess the role of angiogenic factors (vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) in interstitial lung diseases (ILD), such as fibrosing alveolitis, sarcoidosis.

The major characteristics of new bioactive microbial secondary metabolites are summarized in the review. A wide range of new molecular targets are implicated in discovery of new nonantibiotic compounds with some other pharmacological activities (noninfectious diseases). Microorganisms represent fascinating resources due to their production of novel products with broad spectra of bioactivities.

The therapeutic activity of subcutaneous and intraperitoneal nocodazole injections was studied in albino mice with experimental E. granulosus invasion. The animals were intraperitoneally infected with Echinococcus larval cysts (ELC) from a spontaneously inoculated sheep. Nocodazole aqueous suspension (NAS) was administered at the late stage of invasion in two experiments. In one experiment, the treatment was initiated 7.5 months after inoculation. The animals were given daily subcutaneous injections of gradually increasing daily doses (n = 32) from 5 to 20 mg/kg twice weekly for 4 months (the total active ingredient dose was 400 mg/kg). The mice were dissected 3 months after treatment termination. Their autopsy showed that all ELCs or their vast majority were dead in 17 (70.8%) of 24 NAS-treated mice. Among the completely cured mice, there were animals having dead ELCs amounting to 36.9% of the host's weight. In the other experiment, the mice received intraperitoneal treatment 11.5 months after inoculation. They were given NAS injections (n = 2-8) in the total active ingredient dose of 14-126 mg/kg for 4-32 days. The animals were dissected 12-14 months after inoculation. All the detected ELCs were ascertained to be dead in the mice that had received NAS in an active ingredient dose of 87-126 mg/kg and had been dissected 33-81 days after initiation of treatment. The damaging effect of NAS was accompanied by obvious ELC collapse (the ELC collapse index was 57.5-75.9% for all the cured animals).

Among 3-(2-aminopropyl)-1,2,4-thiadiazole derivatives contatining substitution-ready secondary amino group and exhibiting cytotoxic towards rat C 6 glioma cells three compounds with LD 50 values ranged from 6 to 48 мM were chosen. For these compounds amides with docosahexaenoic acid were synthetised and their cytotoxic activity was studied. It was shown that, although docosahexaenoic acid itself was not toxic for C 6 glioma cells, its addition to the amino derivatives of 1,2,4-thiadiazole increased or decreased resultant cytotoxicity. The effect depended on the structure of 1,2,4-thiadiazole substituents. The obtained data show that the acylation of cytotoxic compounds with docosahexaenoic acid does not necessarily lead to the increase of their activity, but sometimes can inactivate a compound. This fact should be taken into account, especially in the case of anti-cancer drug development.

The paper presents the results of a study of the ovarian reserve in young women who received treatment for malignant tumors in childhood and adolescence and are in complete clinical remission. The function of the reproductive system was evaluated by serum concentrations of gonadotropins, estradiol, anti-Müllerian hormone (AMH) and inhibin B. The results were compared to the treatment, patients' age at the beginning of therapy and at the time of the examination. AMH level in serum was the most informative indicator of ovarian reserve in patients treated for malignant tumors.

The results of conservative treatment of 121 patients with endometrial atypical hyperplasia (EAH) and early endometrial cancer (EC) with preservation of fertility are presented. In EAH (n = 56) for 6 months the intrauterine spiral Mirena was used. The effectiveness was 91%, the recurrence rate 16%, pregnancies occurred in 16% of patients. In EC (n = 65) hormone therapy was conducted for 6 months using the intrauterine spiral Mirena and zoladex. The effectiveness was 79%, recurrence rate 22%, pregnancies occurred in 24% of patients. Based on our data and on the results of other studies, the benefits and risks of hormone therapy alone for EAH and EC are discussed in women of reproductive age.

Ovarian cancer is one of the most aggressive malignant tumors in women. The role of hormone therapy in the treatment for ovarian cancer is not fully studied up to now. The literature contains data on the efficacy and safety of treatment with antiestrogens and aromatase inhibitors for recurrent ovarian cancer. The article summarizes the epidemiology, preclinical and clinical studies related to the role of estrogen and aromatase expression in this disease as well as the role of aromatase inhibitors in the treatment for ovarian cancer.

Simultaneously with keeping one of the leading positions in the structure of oncogynecological morbidity, endometrial cancer (EC) presents for many decades 'the food for brains' of cancer endocrinologists. Step by step development of contemporary ideas and collecting the data on mechanisms of hormonal carcinogenesis, the role of excessive estrogenic stimulation and metabolic syndrome/insulin resistance as risk factors for EC, very probable gradual changing of the disease phenotype and significance of genetic damages (with PTEN-mutations as one of the examples), as a consequence point at potential perspectives in the usage of preventive and therapeutic approaches in this important area.