Telomerase is a ribonucleoprotein that synthesizes telomeric repeats and identified as a promising target for anticancer therapy. Here we describe a new compound aITEL1296 as a potent telomerase inhibitor. Its inhibitory activity was a bit higher (IC50 = 0,19 +/- 0,02 ng/ml) than that of BIBR1532, one of the most potent telomerase inhibitors known to date. Besides telomerase inhibition aITEL1296 activated apoptotic mechanisms and effectively suppressed proliferation of tumor cell lines (GI50 = 5,0 +/- 0,2 ng/ml for most sensitive cell line LnCap) but not normal fibroblast cell line.

N epsilon-Nitroso-N epsilon- [N'-(2-chloroethyl)carbamoyl]-L-lysine (I) and N epsilon- [N'-(2-chloroethyl)-N'-nitrosocarbamoyl]-L-lysine (II), the isomers being the constituents of antitumor agent Lysomustine, were obtained by RFHPLC. The study of cytotoxicity of the above compounds against K562 cells showed that the lesions induced by isomer (II) produce a significant cytotoxic effect but can be efficiently repaired by the action of MGMT (O6-methylaguanine DNA methyltransferase). Under similar conditions, the lesions induced by isomer (I) produce substantially smaller effect but are weakly if at all repairable by MGMT. The effects of a clinically approved agent Lysomustine, which is the mixture of isomers (I) and (II), are similar to those of isomer (II). The results obtained point to a different chemical nature of DNA lesions induced by two Lysomustine isomers. Our data indicate that Lysomustine and its isomer (II) can be used for in vitro selection of cells expressing MGMT.

Paclitaxel dosage form on nanoparticles of 200-300 nm based on lactic and glycolic acid copolymer was obtained by the co-precipitation method. The possibility of controlled release of paclitaxel at pH 7.4 for 24 h was studied in vitro. Studies on Jurkat/WT human T-lymphoblastic leukemia cells showed that incorporation of paclitaxel in the nanoparticles led to a 4-fold increase of its cytotoxicity (6.8×10(-6) M) in comparison with paclitaxel solution. The efficiency of compositions containing polysorbate-80 was comparable to that of non-modified nanoparticles containing paclitaxel.

The influence of granulocyte colony-stimulating factor (G-CSF) has been studied on a model of bleomycin-induced pulmonary fibrosis. It is established that G-CSF significantly increases infiltration of alveolar and alveolar duct interstitium by inflammation cells (lymphocytes, neutrophils, plasmocytes) and increases collagen deposition in lung under conditions of bleomycin introduction. Simultaneously with profibrotic and anti-inflammation effects, G-CSF increased the content of granulocyte cells in the bone marrow and peripheral blood, which was related to the stimulation of committed granulocyte precursors in the bone marrow.

With an increasing number of long-term breast cancer survivors, the number of patients experiencing anthracycline-induced cardiotoxicity increas too. Anthracycline--and nonanthracycline-induced cardiac toxicity--clinically significant and frequent adverse event of conservative treatment of cancer. Echocardiogram and multigated acquisition (MUGA) scan--modalities that may overlook early changes that could identify patients at risk for anthracycline-related cardiotoxicity. However, monitoring cardiac function before and during therapy, continuous infusions of drugs, limiting lifetime anthracycline dose, using cardioprotectants such as dexrazoxane, and developing lipid formulations, may decreased risk of cardiotoxicity.

Phosphorylation is the universal regulatory mechanism in key physiological processes such as development, cell differentiation, proliferation, survival and malignant transformation. In this review we analyze serine/threonine protein kinases of the Pim (proviral integration of Moloney virus) family that have been initially discovered in experimental lymphomas. We provide data on gene structure, evolution, functions and substrates of Pim protein kinases. Focusing on Pim-1 as the major isoform, we analyze its role in the biology of hematopoietic malignancies. Pim-1 is a pro-proliferative and pro-survival protein kinase. It is constitutively active due to autophosphorylation, and its downstream partners positively regulate the cell cycle. Pim-1 cooperates with c-Myc oncoprotein in leukemogenesis; furthermore, Pim-1, like the Akt protein kinase, prevents cell death. Thus, Pim kinases are regarded as new therapeutic targets. Finally, we present an original test system f or screening of Pim inhibitors. In this test system the growth of a genetically engineered Escherichia coli strain in the presence of kanamycin is dependent on the phosphorylation of aminoglycoside-3' phosphotransferase VIII by Pim-1: pharmacological inhibition of this phosphorylation increases the bacterial cell lysis.

The authors analyse the efficacy of anti-relapse therapy of juvenile recurring respiratory papillomatosis in 87 children aged from 2 to 15 years with the use of indole-3-carbinol. Prior to inclusion into this study, the patients underwent from 2 to 86 (mean 12 +/- 14) surgical interventions for the ablation of papillomas. The average interval between successive relapses of papillomas ranged between 2 weeks and 12 months (mean 4.9 +/- 2.33 months). The patients remained under observation in the clinic during 2 years--6 years 5 months (mean 44.8 +/- 15.93 months). The duration of therapy with indole-3-carbinol varied from 12 weeks to 2 years (mean 8.9 +/- 4.72 months). The stable remission of pathology was documented in 28.7% of the patients within the 2 to 6 year follow-up period. A significant (1.5-10-fold) increase in the duration of interval between successive relapses occurred in 41.1% of the children. In 29.9% of the patients, therapy produced no apparent clinical effect; 18.4% of them showed an insignificant shortening of the interval between relapses that remained unaltered in the remaining 11.5%. No adverse effects of the treatment were recorded. It is concluded that treatment with indole-3-carbinol can be recommended as a starting therapeutic modality for the management of juvenile recurring respiratory papillomatosis and the reduction of the intervals between relapses of the disease.

The aim of our study was to investigate the effect of recombinant human cytokine EMAP II (endothelial monocyte-activating polypeptide II) on the expression of MGMT gene, encoding repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) in human cell cultures. The influence of EMAP II on cell proliferation was performed using routine MTT assay. Identification of MGMT in cell extracts was performed using Western blot analysis. We used cell lines: A102 (fibroblasts), CB-1 (umbilical cord blood stromal cells), 4BL6 (cells derived from peripheral blood). It was shown that cytokine EMAP II caused induction of MGMT expression in studied human cell lines. There was a decrease in cell number at high concentrations of this cytokine. It was found that the presence of cytokine EMAP II in serum-free growth medium leads to increasing of repair enzyme MGMT expression level in human cells in vitro.

Fifty-four (54) breast cancer patients, receiving tamoxifen, were enrolled into an evaluation of the status of the endometrium. Liquid-based cytology and immuno-cytochemical analysis were used for assessment. Our method proved viable in selective screening for differential diagnosis of endometrial pathology and cancer detection.

This review summarizes the results of long-term researches of the authors who studied the mechanisms of aging and the effectiveness of peptide bioregulators in preventing age-related diseases in laboratory animals. The data is provided on the evaluation of peptides effects which were produced using the most modern techniques in scientific institutions in Russia and abroad. The main attention is paid to the ability of peptide bioregulators to increase the life span and inhibit the carcinogenesis in animals.

The effect of dopamine (DA) on the viability and morphology of cultured tumor THP-1 cells (human acute monocytic leukemia) was studied. DA in concentration of 10(-5) M had virtually no effect on the culture, while in concentration of 10(-4) M to 10(-3) M it stopped the growth and caused a sharp increase in cell death after 24 and 48 hours. Incubation with DA reduced the cell diameter, progressively increased their vacuolization and intensity of fluorescence after treatment by Falck method. Electron microscopical study has shown that cells exposed for 1 day to DA in the concentrations starting with 10(-4) M, demonstrated smoothing of their surface with the disappearance of microvilli and clasmatosis vesicles, actin filaments perforating the plasma membrane, the emergence of an increasingly dense network of filaments in the cytosole and karyoplasm and, finally, apoptotic cell death. It is suggested that the oncotherapeutic cellular target for DA is a cytosolic G-actin, which at a certain DA concentration, turns into filaments that damage the cells, break the cell cycle and cause cell death.

Sixty one male 129/Sv mice were exposed to a single intraperitoneal injection of 1 g per kilo of urethane dissolved in 0.9% normal saline. Starting the next day from the injection the study group mice were given 1200 mg metformin per liter of drinking water 5 days a week for 26 weeks. The control group mice received pure drinking water. Six months after the urethane treatment the mice were killed and the morphology samples were taken. Twenty five of 31 (96.7%) control group mice developed tumors (lung adenomas and thymic lymphomas), while tumor development was observed in 25 of 31 (80.7%; p<0.05) mice exposed to metformin. Solid or trabecular lung adenomas developed in 90% of the control group mice and in 77% of the metformin group mice (p=0.119). Therefore, it is a first evidence of tumor-inhibitory effect of metformin in mice.

This study compares the anti-carcinogenic activity of calcium glucarate, potassium glucarate, and potassium glucuronate in cervix and esophagus induced cancer murine models. The cervical cancer induction was performed by tampons moistened with 0.1% solution of 7,12-dimethylbenz(a) anthracene (DMBA) applied intravaginally twice a week for 6 weeks in mice. Esophageal cancer was induced by oral administration of 10 mg of N-methyl-N-benzylnitrosoamine (MBNA) with drinking water for 1 month in rats. The 2 g per kilo of studied substances was administered orally with food immediately after the exposure to cancerogens for the period of 11 months. Compared to the control group the calcium glucarate, potassium glucarate and potassium glucuronate introduction reduced the incidence of cervical cancers by 20.4%, 32.1%, and 30.0% (p<0.05), accordingly; calcium glucarate introduction decreased only the medium number of the esophagus tumors by 44.3% (p<0.05); potassium glucarate and potassium glucuronate reduced the incidence of esophagus tumors by 35.1% and 61.3% (p<0.05) and their number by 32% and 58.5% (p<0.05), accordingly. Compared with calcium glucarate, potassium salts of glucaric and glucuronic acids inhibit cervical and esophageal carcinogenesis more effectively.

Research during the past decade has shown that epigenetic events have a key role in carcinogenesis and tumour progression. Histone deacetylase inhibitors (HDACi) comprise structurally diverse compounds that are a group of targeted epigenetic anticancer agents. Here we explored the in vitro efficacy of HDACi such as sodium butyrate (BuNa), valproic acid (VaNa) and several novel HDAC inhibitors for the treatment of cancer. Both BuNa and VaNa inhibited cancer cell proliferation in a time--and dose-dependent fashion. In the present study we demonstrated the significant effect of two novel HDACi, Adipo or BuNHOH, able to induce apoptosis of cancer cells, but not of normal line. Since HDAC inhibitors have been proposed as radio--or chemosensitizers in cancer therapy, we have studied the radiosensitizing effect of sodium butyrate on cancer cells. The combination of BuNa and radiation significantly inhibited tumor cell growth. Besides, combining Cisplatin or Gemzar with HDAC inhibitors results in synergistic antiproliferative activity that could be therapeutically exploited. These results suggest that HDACi acts as an antitumor agent and that combining HDAC inhibitors with radio or--chemotherapeutic strategy may provide a novel chemotherapeutic treatment of cancers insensitive to traditional antitumor agents.

In this mini-review the basic evidence about anticancer properties of ursolic acid (UA), the compound belonging to the class of triterpenoids, is given. Beside inhibiting tumor cell growth in vitro and in vivo and activating of apoptosis, UA (as well as some other related and not related compounds) is capable to induce PTEN (a tumor suppressor mutation of which is rather often discovered in human tumors including endometrial cancer type I) and amount/activity of brown fat. The latter action may explain obesity-preventing capacity of UA that also may lead to an additional antiblastomogenic effect.