Paclitaxel (single intravenous injection in a maximum tolerated dose of 4.6 mg/kg) to white outbred rats causes bone marrow hypoplasia, increased granulocyte and erythroid cell mitosis (metaphase-anaphase transition), and moderate pancytopenia developments in peripheral blood (hypoplastic anemia, deep, short-term neutropenia, lymphopenia and thrombocytopenia) in the first hours after injection. A considerable increase of polyploidy (4n) cells and a moderate increase in the structural changes (chromatid deletions) of chromosomes was observed on bone marrow metaphase plates in 24 h. The drug introduction causes earlier increase in the rate of thymus cells mitosis, a growth in the number of thymocytes with apoptosis signs, and a moderate decrease in the thymus and spleen weight. All changes are reversible. Long-term (90 days after injection) observation revealed decreased lymphocyte count in the peripheral blood and bone marrow and earlier thymus involution.

A4 clone cells, received by CD95-mediated selection from the parental line of Jurkat T-lymphoblast human leukosis, lost their ability of apoptosis as a result of programmed cell death mechanism breakdown. The complex of their acquired phenotypic properties meets tumor progression criteria: oxidative stress resistance, active immune suppression, and low requirement for growth factors. The loss of A4 cell ability of apoptosis is accompanied by acquisition of the phenotype of multiple medication resistance to a wide spectrum of antineoplastic chemotherapeutic drugs and cytotoxins.

Effect of combined use of doxorubicin and ceftriaxone on 5 strains of Staphylococcus aureus (standard S. aureus ATCC 29213 and 4 isolated strains) was studied. The method of passages in meat-pepton broth with constant and increasing concentrations of ceftriaxone in presence of 1/2 and 1/4 minimum inhibitory concentration of doxorubicin was used. It has been shown that doxorubicin in such concentrations does not influence on the development of resistance of tested strains to ceftriaxone. The combination of doxorubicin as anti-tumor drug with intercalary action and ceftriaxone does not increase the risk of development of resistance of staphylococci to antibiotics, which has a matter during their combined use.

The effect of different doses of synthetic antioxidant beta-(4-hydroxy-3,5-ditertbutylphenyl)propionic acid (phenosan) on the development of spontaneous leukemia in AKR mice was studied. The drug efficiency was determined from the survival curves, animal life spans, and the incidence of leukemia. Phenosan exhibited a pronounced antitumor activity at therapeutic (10(-4) mol/kg, 4 administrations) and ultra-low (10(-14) mol/kg, 4 administrations) doses. The dose of 10(-4) mol/kg proved most efficient to increase the life span of the shortlived subpopulation, while the dose of 10(-14) mol/kg increased the life span of the long-lived subpopulation. The ultra-low dose of the drug seems promising as a prophylactic agent.

The data on the discovery, specific features and evolution of the aftereffects of functioning in the cells of the ABC-transporters Pgp, MRP and BCRP, the markers of multiple drug resistance (MDRABC), are discussed. The results of the estimate of the MDRABC phenotype of human solid tumors were critically analyzed using different methodic approaches. It was shown that the frequency of the MDRABC phenotype detection by expression of the genes, encoding the ABC-transporter synthesis, was higher than that in detection of transport proteins in the cell. It was concluded that the only adequate clinical method for diagnosis of the MDRABC phenotype could be differential estimate of the functional activity of the ABC-transporters controlling not only the drug release to the cell, but also the drug intracellular compartmentization or division between the cytoplasm and nucleus.

An actinomycete strain designated as Actinomadura sp. INA 654 was isolated from a chernozem soil sample in the Voronezh Region by the soil sample treatment with millimetric waves (EHF band). The strain produced an antibiotic complex of 2 components, named A-654-I and A-654-II. Investigation of their physico-chemical properties showed that A-654-I was identical to echinomycin, a heteropeptide lactone of the quinoxaline group with antitumor activity, while A-654-II proved to be likely a new natural compound. Production of echinomycin by a representative of the Actinomadura genus was detected for the first time. Up to now, only representatives of the Streptomyces genus were known to produce echinomycin.

A principle possibility of antitumour activity test in bacterial system represented by Escherichia coil of the wild type and its MS2-induced mutant has been shown. The initial bacterial strain is an indicator of toxic properties of the tested substances and the mutant one is a specific test-culture modelling a tumour cell. The comparison of the data described for eucaryotes with the data obtained using the proposed bacterial test system confirms an adequate response of both strains to the substances with the proved antitumour properties. The data are considered as very promising for the further improvement of this test system towards its application for primary screening of antitumour substances.

The results of our study showed, that long-term combined medical treatment of benign prostatic hyperplasia (Finasteride 5 mg/day + Tamsulosin 0.4 mg/day) significantly decreases values of IPSS and residual urine volume (RUV) in patients, which basic level of bFGF in serum does not exceed 5.9 pg/ml. On the other hand pharmacological treatment was insufficient in patients with bFGF basic level equal or more than 5.9 pg/ml; values of IPSS and RUV did not decrease.

We have recently synthesized a lipid conjugate of the anticancer agent methotrexate (MTX-DG) and showed that the conjugate is quantitatively included in the lipid bilayer of liposomes prepared by a standard extrusion technique from an 8 : 1 : 1 (mol) egg phosphatidylcholine-yeast phosphatidylinositol-MTX-DG mixture. Both the size of liposomes (126 +/- 30 nm) and the MTX-DG concentration (4.4 mM) are relevant for systemic injections in mammals. The liposomal formulation of MTX-DG was shown to overcome the resistance of tumor cells in vitro to methotrexate: the cytotoxic activities (IC50) of MTX in cultures of the human T-lymphoblastic leukemia cell line CEM-CCRF and the MTX-resistant subline CEM/MTX were 0.075 +/- 0.005 and 16.4 +/- 4.9 microM, respectively, while, in the case of liposomes loaded with MTX-DG, the IC50 values were much closer: 0.77 +/- 0.06 and 3.8 +/- 1.9 microM.

Inactivation of tumor suppressor p53 accompanies the majority of human malignancies. Restoration of p53 function causes death of tumor cells and is potentially suitable for gene therapy of cancer. In cervical carcinoma, human papilloma virus (HPV) E6 facilitates proteasomal degradation of p53. Hence, a possible approach to p53 reactivation is the use of small molecules suppressing the function of viral proteins. HeLa cervical carcinoma cells (HPV-18) with a reporter construct containing the b-galactosidase gene under the control of a p53-responsive promoter were used as a test system to screen a library of small molecules for restoration of the transcriptional activity of p53. The effect of the two most active compounds was studied with cell lines differing in the state of p53-dependent signaling pathways. The compounds each specifically activated p53 in cells expressing HPV-18 and, to a lesser extent, HPV-16 and exerted no effect on control p53-negative cells or cells with the intact p53-dependent pathways. Activation of p53 in cervical carcinoma cells was accompanied by induction of p53-dependent CDKN1 (p21), inhibition of cell proliferation, and induction of apoptosis. In addition, the two compounds dramatically decreased transcription of the HPV genome, which was assumed to cause p53 reactivation. The compounds were low-toxic for normal cells and can be considered as prototypes of new anticancer drugs.

Effect of the inhibitors of polyamines biosynthesis on completely or partially hormone-dependant breast tumors (mouse Ca755 carcinoma and Walker W-256 carcinosarcoma) is essentially special: in contrary to hormone-dependant tumors, this effect may be not only breaking but stimulating as well. Change-over from one to another mode of reaction is conditioned, most probable, by hormonal status, which is determined by one or another estral cycle phase. Biochemical mechanisms of this change-over are closely connected with polyamines metabolism, namely the degree of polyamines (especially spermine) interconvertion and physiological reactivity level of the system controlling expression of ornithin-decarboxilase. At that, the first of these pathways is predominant for completely hormone-dependant Ca755 and the second one -for partially hormone-dependant W-256.

(22R,23R)-22,23-dihydroxystigmast-4-en-3-one, (22R,23R)-22,23-dihydroxystigmast-4-en-3,6-dione, (22R,23R)-3beta,5alpha,6beta,22,23-pentahydroxystigmastane, (22R,23R)-5alpha,6alpha-oxido-3beta,22,23-trihydroxystigmastane, (22R,23R)-5beta,6beta-oxido-3beta,22,23-trihydroxystigmastane, and (22R,23R)-3beta,6beta,22,23-tetrahydroxystigmast-4-ene were synthesized. Their cytotoxicities were comparatively studied using the MCF-7 line of carcinoma cells of human mammary gland and cells of human hepatoma of the Hep G2 line.

The study was concerned with identification of predictive value of p53 expression on sensitivity to tamoxifen in breast cancer management. Estrogen receptor-positive cell line MCF-7 was used to establish p53 expression influence on the rate of cell proliferation after tamoxifen. The investigation demonstrated the absence of that effect when p53 was silenced.

The genotoxicity of doxorubicin was assessed by the induction of ribonucleotide reductase gene expression and by the oxidative stress induction in Saccharomyces cerevisiae as a eukaryote cell model. Doxorubicin induced dose-dependent inhibition of cell proliferation, increased the intracell concentration of GSH and GSSG, and did not significantly influence the malonic dialdehyde concentration. Doxorubicin activated (independently of the concentration) ribonucleotide reductase gene expression, thus increasing GSH concentration. The increase in GSSG concentration is probably indicative of the development of oxidative stress in Saccharomyces cerevisiae cells, although this is not accompanied by an increase the MDA concentration in the cells.

The idea of microtubules (MTs) as of passive railway tracks, along which transport vesicles travel by use of motor proteins, is widely accepted. In the present work the organization of MT system during EGF-receptor endocytosis was investigated by indirect double immunofluorescence in HeLa and A431 cell lines. Stimulation of cells with EGF resulted in formation of EGF receptor-containing peripheral vesicular endosomes. During time course of endocytosis the endosomes tended to concentrate in juxtranuclear region close to MTOC. This translocation was dependent on MTs since nocodazole treatment resulted in endosomes' scattering throughout the cytoplasm. Parallel staining of the cells with tubulin antibody has revealed significant remodeling of MTs organization during endocytosis. At early stages MTs demonstrated slight retraction at the cell periphery and the increasing intensity of tubulin fluorescence in the juxtranuclear region. Later on, long individual MTs disappeared and peripheral cytoplasm show diffuse staining in combination with a meshwork of short MT fragments. This stage correlated with EGFR localization in juxtranuclear endosomes. Disappearance of EGFR-positive staining due to its lysosomal degradation occurred in parallel to reestablishment of radial MT system. Possible functional significance of described alterations in organization of tubulin cytoskeleton is discussed.

To comparatively assess the capabilities of currently available instrumental studies in the diagnosis of early cardiac performance changes in patients with lymph tumors at different stages of treatment and to study the myocardial histomorphological pattern in relation to the intensity of the therapy performed (as evidenced by sectional studies).

The fungus Fusarium bulbigenum var. blasticola in which secondary tumor-like formations appear under certain conditions in aging was used as a new test system to examine the action of antitumor preparations. Free radicals in the primary mycelium and tumor-like formations without introduction of preparations (control samples) and after the introduction of preparation into the cultivation medium of the fungus have been studied by EPR spectroscopy. The EPR spectra of the fungus represent single, somewhat asymmetrical lines with a width of deltaH = 0.4 divided by 0.6 mT and g = 2.0036 +/- 0.006, which enabled one to assign the paramagnetic centers observed to melanine radicals. It was found that the concentration of free radicals in tumor-like formations is always higher than in the primary mycelium, which may be related to intensive metabolism in tumor-like formations. It has been established that several antitumor preparations (fluorouracil, hydrea, methotrexat, and vepezide) completely inhibit the growth of tumor-like formations. Another group of preparations (cyclophosphanum, dacarbazin, adriablastin, and vinblastin), on the contrary, stimulate their growth, which is accompanied by an increase in the concentration of free radicals in cells of the primary mycelium and tumor-like formations. The preparations of the third group (mercaptopurine, lanvis, and farmorubicin), despite the increased level of free radicals in cells, have a weak inhibitory effect. It has been shown that, in the concentration range studied, vitamins B2, B12, C, and PP stimulate the growth of tumor-like formations, and, when used in combination with antitumor preparations, enhance or reduce the inhibitory properties of these preparations.

We compared the capacity of superlow-dose of antibodies to erythropoietin (Poetam) and recombinant erythropoietin (Recormon) to stimulate the recovery of adriamycin-suppressed erythropoiesis in mice. Both preparations exhibited high erythron activation capacity and considerably increased the content of erythrocytes and reticulocytes in the peripheral blood and content of erythrokaryocytes and erythroid precursors in the hemopoietic tissue of experimental animals. The effect of Recormon manifested immediately after injection, while the effect of Poetam was somewhat delayed, but more lasting (due to activation of host erythropoietin system).

We studied the role of VEGF signal pathway in autocrine regulation of tumor cell growth and survival under conditions of hypoxia. Hypoxia-resistant CaOv/H substrain with high level of VEGF-A secretion was obtained by long-term culturing of CaOv ovarian adenocarcinoma cells with CoCl2 (hypoxia inductor). VEGF-A directly participates in autocrine regulation of CaOv cell growth, including the maintenance of cell growth under conditions of hypoxia or cytostatic treatment. On the other hand, CaOv/H cells retain high apoptotic potential and are characterized by high expression of p27Kip1 (cyclin-dependent kinase inhibitor), which attests to possible involvement of this inhibitor into the regulation of apoptotic response of cells under conditions of hypoxia.