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.

Testicular tumors illustrate curable cancer, but 25% patients are resistant to standard therapy. High-dose chemotherapy (HDC) is promising therapy for germ-cell tumors with poor prognosis. HDC and transplantation of autologous stem cells were performed in 13 patients with germ-cell testicular tumors (GTT). In 6 patients of group 1 HDC was first-line treatment in poor prognosis, in 7 patients (group 2) it was a salvage treatment after recurrences. Patients of group 1 had longer mean survival than those of group 2 (31.3 and 11 months, respectively; p = 0.136). Two patients died of HDC complications. Neurological, hematological and other complications occurred. In spite of 50-90% remission after HDC, multicenter prospective randomized trials will give final conclusion on effectiveness of HDC which must be performed in special clinics having many specialists in their staff (urologists, oncologists, chemotherapists, etc.).

To quantitatively determine minimal residual disease (MRD) by real-time polymerase chain reaction (PCR) in patients with a chronic phase (CP) of chronic myeloid leukemia (CML).

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).

Surgery was used in the treatment of 194 patients with tumors of the oral cavity and throat. In 110 of them the treatment was combined (radiotherapy and surgery) and in 84 - complex (polychemotherapy + surgery + postoperative radiotherapy). Characteristics of surgeries are compared. It is demonstrated that number of function-preserving operations in patients given complex treatment was 86.9%, combined treatment - 70.9%.

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.

The effects of mexidol and emoxypine on some indexes of endotoxicosis and weighted characteristics of tumor carrier during experimental neoplasia have been studied under the conditions of therapy using antracycline antibiotic rubomycin.

Mechanisms of the myelotoxic action of doxorubicin associated with changes in the expression and functional activity of P2X7 receptors have been assessed. The acute and subacute exposure of bone marrow cells to doxorubicin in vivo changed the expression of P2X7, altered the intracellular and extracellular ATP concentrations, and modulated the process of programmed cell death. These changes were associated with transformed susceptibility of hemopoietic cells to the apoptogenic action of ATP. Various possible mechanisms of realization of the apoptogenic action of ATP during acute and subacute exposure to doxorubicin are discussed.

New water-soluble conjugates in the form of Schiff bases (DGM-1 and DGM-2) were prepared by the interaction of water-soluble periodate-oxidized galactomannan with doxorubicin or N-(L-lysyl)doxorubicin, respectively. The water-soluble galactomannan (DAVANAT a commercial product of Pro-Pharmaceuticals company) was obtained by partial acidic hydrolysis of high-molecular-mass galactomannan from Cyamopsis tetragonoloba (guar gum) seeds. The conjugate stability was studied in aqueous solutions. The DGM-1 antiproliferative activity was comparable with that of doxorubicin on three models: cell lines of murine melanoma B 16-F1, human breast cancer MCF-7 (HTB-22), and human colon cancer HT-29 (HTB-38). DGM-2 was poorly active in all the three tests. DGM- 1 can thus be regarded as a high-molecular-mass depot form of doxorubicin.

A procedure is proposed to contrast a clear solution of the cytostatic agent 5-fluorouracil during subconjunctival administration early after surgery for glaucoma in order to prevent hyperscarring. For this, after dissolution of 5-fluorouracil with 0.1% dexamethasone solution, 0.05 ml of 0.08% trypan blue solution was added to an injection syringe until the mixture produced a uniform light blue color. 0.1-0.2 ml of the mixture was subconjunctivally injected. The proposed procedure makes it possible to visualize the site of injection with a high degree of reliability: the penetration of the agent into the given area, the area of its spread, and the volume of the agent's administration, to view external filtration and possible intrachamber flux, and to provide information on the topography of formed outflow tracts.

The effect of the antitumor antibiotic doxorubicin on the mechanisms of intracellular signal transduction in the region of free water dispersion has been investigated by the EHF-dielectrometry method. It was shown that the drug whose main target is nuclear DNA has a rather strong influence on free cells of the nucleus, the functions of catecholamine receptors, and the complex of adenylate cyclase with the cytoskeleton. The effect of the drug has significant individual and species differences. Variants of tests for individual selection of doses in the therapeutic practice are suggested.

Using histological, morphometric, histochemical and immunocytochemical methods, the effect of cytotoxic treatment on structural and functional characteristics of the epithelium of esophageal mucosa was studied in mice together with the reversibility of the changes induced by cytotoxic drug. Fourfold intraperitoneal injection of cyclophosphamide (400 mg/kg of body mass) resulted in such morpho-functional changes, as thickening of epithelial layer, increase in proportion of its stratum corneum and its loosening, disturbances in cornification process, hyperkeratosis, vacuolization of cell cytoplasm in stratum basale and stratum spinosum, interstitial edema, nuclear hypertrophy and parakeratosis. Mitotic activity and the activity of NADH-diaphorase were significantly reduced, while the number of PCNA' cells was increased. Cyclophosphamide had no significant affect on the concentration of total proteins. 15 days after the discontinuation of cytostatic treatment, most of the indexes did not return to normal values, indicating profound disturbances in the esophageal epithelium.

Sensitivity to the lethal action of the anticancer substance cisplatin was studied in the yeast mutants himl, hsm2, hsm3, and hsm6, deficient for repair of spontaneous and induced mutations. The himl and hsm3 mutants were as resistant to the agent under study as the wild-type strain. The survival of the double mutant rad2 hsm3 was higher than that of the single mutant rad2. The hsm2 and hsm6 mutants were more cisplatin-sensitive than the wild type. Cisplatin was shown to have high mutagenic and recombinogenic effects on yeast cells.