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.

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.

The effects of naturally-occuring polyphenols, resveratrol and quercetin, on cell viability and apoptosis were studied in Namalwa B-cell lymphoma line. Apoptotic cells were identified using DNA flow cytometric analysis and 1H NMR spectroscopy. The effects of the agents on the cell cycle kinetics and activation of caspase-3 were examined. Both resveratrol and quercetin induced apoptosis in Namalwa cells as demonstrated by the increased number of hypodiploid cells, elevated level of mobile lipid domains and caspase-3 activation. Treatment with 40 microM of resveratrol for 48 h resulted in time-dependent cell-cycle arrest at G0/G1. In contrast, upon quercetin treatment Namalwa cells accumulated in G2/M. Obtained results suggest that resveratrol and quercetin induced caspase-dependent apoptosis in human malignant lymphoid cells in vitro. These findings provide a rationale for further studies of in vivo effects of those polyphenols.

It has been established that alpha-tocopheryl succinate in concenrations 10-100 microM inhibits in a dose-dependent manner the viability of primary culture rats thymocytes and causes the DNA internucleosomal degradation that testifies to apoptotic way of thymocytes destruction. These effects were accompanied by an enhanced production of intracellular superoxide. This is the first report demonstrating that apoptosis induced by alpha-tocopheryl succinate was accompanied by a dose-dependent inhibition of mitochondrial succinate dehydrogenase. Known apoptosis inducers--actinomicin D, staurosporin and hydrogen peroxide decreased a cell survival but neither induced any significant changes in succinate dehydrogenase activity which means that this effect is characteristic only of alpha-tocopheryl succinate and seems to be an important event triggering the apoptotic response by it. It was supposed that alpha-tocopheryl succinate might appear as a pseudosubstrate for mitochondrial succinate dehydrogenase leading to its inhibition, dysfunction of the mitochondrial electron transport chain, generation of reactive oxygen species and iduction of apoptosis.

The anticancer drug Cancerolysin has been developed, by using the mutant Adel2 variant of human adenovirus serotype 5 designed at the State Research Center of Virology and Biotechnology. Cancerolysin possesses a high degree of replication activity for complementary cells 293 and p53-deficient tumor cells and, at the same time, has significant replication limitations in normal human cells. Preclinical studies of the drug on laboratory animals (mice, rabbits, guinea pigs) have demonstrated its harmlessness and safety. When stored at -40 and -70 degrees C, the drug showed no significant activity throughout the control observational period (1 year).

This article deals with the lycopene of mycelial fungi. It pays special attention to its physical and chemical properties, occurrence in nature, biological functions, and the biotechnology of lycopene production. Data are presented concerning the medically important properties of lycopene and the drug Mycolycopene prepared on its basis. Its prospective use in the therapy of prostate cancers is discussed.

Anticarcinogenic action of dietary supplement Pheocarpin and its active component Natural Coniferous Complex (NCC), in particular, has been studied. Pheocarpin and NCC efficiently inhibited tumorigenesis in the mammary gland, large bowel, skin, cervix uteri and lungs. Pheocarpin offers considerable advantage as a means of reducing the risk of malignant disease.

Non-inbred SHR/u 3-month old mice were injected a single dose of urethane 1 g/kg, intraperitoneally. Beginning from day I after injection, they received melatonin 20 mg/l or 2 mg/l with drinking water at nighttime. After 28 days of the experiments, mice were sacrificed, lung adenomas counted and examined morphologically. Samples of blood and ling tissue were taken from each group and assayed for malonic dialdehyde (MDA) and catalase level. Tumor count of lung adenomas in the untreated group (control) was 23 +/- 2.63, melatonin 20 mg/l--14 +/- 1.2 (p < 0.01) and melatonin 2 mg/l--11 +/- 0.72 (p < 0.01). Urethane-treated mice revealed increased levels of MDA (62%) and catalase (70.7%) in blood-serum and in lung tissue (36.5%) as compared with control. Melatonin treatment significantly lowered concentrations of MDA in blood-serum and catalase (blood-serum and lung) rather than in the lung bearing urethane-induced tumor. Antitumor and antioxidant effect of relatively low dosage of melatonin appeared to be more effective than those of a larger one.

Procedure for microencapsulation providing stable formation of high quality microspheres was designed. Conditions for deposition of the anthracycline antibiotic daunorubicin to polymer matrix were developed and microsheres loaded with various quantities of the drug were prepared. The kinetics of the in vitro and in vivo release of daunorubicin from the microsheres was studied. The rate of the rubomycin release to the medium in vitro (balanced phosphate buffer at 37.8 degrees C) in a 300-hour experiment directly depended on the quantity of the incorporated drug and averaged 0.81 x 10(-4) to 2.3 x 10(-4) mcg/ml x h. The experiment on laboratory animals with intraperitoneal administration of the rubomycin microsperes showed that the drug remained in the blood and abdominal liquid for a long time (up to 10 days). Possible control of the quantity of the rubomycin encapsulation to the polymer matrix, no sharp efflux of the drug at the early stages of the observation and low rate of the drug release to the medium allowed to conclude that the use of the biodegradable polymer microsperes as carriers of the high toxic antibiotic providing its prolonged action was prospective.

Acute toxicity of L-lysine-alpha-oxidase, an antitumor enzyme of fungal origin was studied. After intravenous administration in a dose of 3000 U/kg the substance induced no signs of intoxication in the laboratory animals or their death. Direct dependence of the vessel permeability increase on the enzyme concentration was determined. In experiments on rabbits and guinea pigs L-lysine-alpha-oxidase showed no local irritating effect.

The cytostatic drug cyclophosphamide (CPA) in high dosage suppressed hemopoiesis by causing multiple double-strand breaks to occur in hemopoietic cell DNA and leading to mutation, chromosomal abberations and finally cell death. We tested fragmented DNA drugs for an ability of CPA to protect murine leukopoiesis on an assumption that once exogenous fragmented DNA had infiltrated into a cell, it might integrate with chromosomal DNA through homologous recombinations thus repairing damaged segments. DNA drugs did promote repair of leukocyte count in murine peripheral blood with leukopoiesis being suppressed by CPA administration. The levels of DNA derived from murine organs and human placenta were higher than those from salmon roe. Tumor growth was significantly inhibited following injection of placental DNA into mice bearing intramuscularly transplanted lymphosarcoma. Antitumor effect of combined CPA and DNA treatment was much higher than after CPA alone.

Luliberin analogues modified at the N-terminus were synthesized to search for drugs exerting a cytotoxic effect on cells of hormone-dependent tumors. A synthetic scheme effective in the preparation of analogues containing fatty acid residues was proposed. The cytotoxic effect of the peptides was studied on a number of cell lines of human tumors in vitro. The dependence of the antitumor effect on the length of peptide chain, amino acid sequence, and structure of the N-terminal group was demonstrated. Modification with palmitic acid was found to result in highly active compounds in the case of analogues containing more than ten aa, whereas modifications with lauric, caproic, or trimethylacetic acid led to compounds with significantly lower activities. Analogues of luliberin containing a palmitic acid residue and effectively inhibiting the growth of tumor cells in vitro were synthesized.

Roncoleukin--recombinant IL-2--was studied with a view to application for LAK therapy. Lymph of ductus thoracicus from ovarian cancer patients receiving adjuvant autolymphochemotherapy was used as source of lymphocytes. Immunobiologic activity of lymphocytes was assayed after 30-minutes incubation with roncoleukin and 24- or 48-hours culturing. The investigation established an increase in T-cell proliferation, autocrine stimulation of IL-2 production, growth of NK-cells cytotoxicity, immediate cytotoxic effect on K562 target cells culture and such sensitizing effect as roncoleukin's potential to boost its susceptibility to NK-lysis. LAK-therapy was used as a component of complex treatment of ovarian cancer (8). Our method has a future in dealing with the present pathology.