It has been shown by the method of fluorescent analysis that the rate of hydrogen peroxide generation in human U251 glioma cells under the effect of lipophilic (menadione) or hydrophilic (vikasol) analogues of vitamin K3 was different. Analyzing experimental data we can conclude that menadione underwent one- and two-electron reduction by intracellular reductases in glioma cells. Reduced forms of menadione interact with molecular oxygen leading to reactive oxygen species (ROS) generation. The theoretical model of ROS generation including two competitive processes of one- and two-electron reduction of menadione has been proposed. Rate constants of ROS generation mediated by one-electron reduction process have been estimated.

Published data on the main types of reagents capable of introducing covalent interstrand cross links into nucleic acids (NA) are summarized in the present review. The reactivity of cross-linking agents, their preferred binding sites, and methods of determining the cross-link localization in a duplex are discussed. Cell response to DNA cross linking, namely, the blocking of replication and transcription, the initiation of reparation processes, and apoptotic death of the cell, are analyzed, as well as the use of cross-linking reagents in therapy and molecular biology.

Cytotoxic properties of a liposomal form of the HLDF6 hexapeptide, representing an HL-60 cell differentiation factor fragment, have been studied on a murine primary lymphosarcoma cell culture. It is established that the liposomal HLDF6 peptide is capable of inhibiting proliferation and enhancing death of the cells of both LS and RLS lymphosarcoma strains distinguished by their sensitivity to cytostatic agents. The effect of the preparation is determined by its antiproliferative and apoptogenic actions on the cells. Free HLDF6 peptide showed a lower cytotoxic activity with respect to the tumor cells as compared to the liposomal preparation.

to analyze the efficacy of RFC (rituximab, fludarabine, and cyclophosphan), FCM (fludarabine, cyclophosphan, and mitoxantrone), and FC (fludarabine and cyclophosphan) treatment programs in patients with chronic lymphocytic leukemia (CLL) in an open-labeled comparative controlled investigation.

Tumor regression was reported in 20-30% of patients with inoperable non-small-cell lung cancer (NSLC) following standard first-line chemotherapy. Clinical trials with second-line gefitinib (Iressa) showed a strikingly high response in patients with mutated EGFR. However, clinical experience with gefitinib as first-line therapy had been limited to small-scale trials mostly among subjects of Asian origin. Our study was not associated with the drug manufacturer and included 25 chemotherapy-naive patients with mutated EGFR inoperable lung adenocarcinoma. Standard dose was 250 mg/day. Complete response was observed in 1 patient (4%), partial--11 (44%), sustained stabilization--13 (52%); median time until tumor progression--186 days. Median overall survival failed to be registered within the duration of the study. Among most frequent side-effects were skin rash (19; 76%) and diarrhea (14; 56%): marked side-effect -toxicity grade III (4; 16%). Gefitinib appeared highly efficient and tolerable and may be recommended as first-line treatment of mutated EGFR inoperable NSLC.

The effects of phorbol ether (PMA) and ionizing radiation on multidrug resistance (MDR) of human larynx cancer cells HEp-2 and the dependences of these effects on protein kinase C (PKC) activity and reactive oxygen species (ROS) production were studied. MDR was determined by transport rate of rhodamine 123 off cells and production of ROS in cells was measured by means of 2'7'-dichlorodigidrofuorescein oxidation to fluorescent 2',7'-dichlorofluorescein. ROS production was increased in cells at PMA treatment. This increase was caused by PKC dependent activation of NADPH-oxidase because the ROS increase suppressed completely with PKC and oxidase inhibitors. It was shown that tumor cell MDR was increased 16 h after PMA (100 nM) and radiation (1 Gy) treatment. The MDR increase depends on PKC activity and ROS increase in cells at both influences since PKC inhibitor and antioxidant, lipoic acid suppressed MDR increase. The obtained data are in accordance with hypothesis about the necessity of activation both signalization and stress reaction for initiation of transcription of transport protein genes which responsible for MDR of tumor cells.

Clinical experience of the authors on patients with Peyronie's disease shows that intraplaque therapy with verapamil and interferon and a malignant course of the disease can result in shortening of the penis (4 and 1 cases were observed, respectively). The length of the penis diminished by 30 to 50%. The patients were treated with graft corporoplasty with endoprosthesis of the penis. Basing on the experience with these cases the following conclusions were made: intraplaque injections are hard to perform and can provoke progression of the disease; long-term conservative treatment for stabilization of the active stage of Peyronie's disease can lead to shortening of the penis; in malignant course of the disease and progressive shortening of the penis surgical policy is justified despite "acute" phase of the disease.

The effects of indol-3-carbinol and epigallocatexin-3-gallate on alteration and reparation in the urethra were studied in 30 male Shinshilla rabbits. From the observation day 2 the rabbits were fed with indol-3-carbinol and epigallocatexin-3-gallate in addition to standard diet. Microcirculation was assessed with a laser analyzer of capillary circulation LAKK-01 which detected earlier recovery of microcirculation in the group of the animals fed with indol-3-carbinol and epigallocatexin-3-gallate. Thus, antioxidant and antiproliferative properties of indol-3-carbinol and epigallocatexin-3-gallate improve alteration and reparation in affected urethra due to development of soft elastic connective tissue with better capillary circulation.

Specific antiangiogenic therapy for exudative age-related macular degeneration (AMD) aims at suppressing the growth of choroidal neovascularization. Bevacizumab, an antibody to vascular endothelial growth factor, is one of the agents that specifically inhibit angiogenesis. The results of using bevacizumab in choroidal neovascularization induced by AMD are analyzed. Bevacizumab was administered into the vitreous body of 56 patients (60 eyes) in a dose of 1.25 mg; its injections were repeated if the need arose in disease recurrence. The follow-up time was 6 to 12 months. Following 6 months, visual preservation not below the baseline level was noted in 86% of cases; in this period a significant visual improvement was stated in 46% of cases. Fluorescence angiography showed decreased dye leakage in most cases, which correlated with the lower retinal thickness revealed by optical coherence tomography. There were no serious complications. Intravitreal administration of bevacizumab is the method of choice in treating exudative AMD and requires further investigation.

A number of interleukins and iron metabolic parameters were studied in acute leukemia over time. Regulation of hemopoiesis and the cytokine network has been found to be impaired, which appears as the increased synthesis of ferritin and hepsidin by macrophages that are activated by imbalance in the cytokine network. A severe impairment of the parameters responsible for a regulatory process is shown to occur in leukemia. There is no complete normalization of these parameters during hematological remission, which is likely to lead to a further relapse of leukemic process.

The redistribution of actinomycin from hairpin oligonucleotide HP1 to dissolved DNA and DNA inside the cell has been discovered and investigated. It was found that the penetration of the antibiotic in a complex with HP1 into cancer cells takes place more effectively than that of the antibiotic separately. It is suggested that hairpin oligonucleotides can serve as molecular carriers of heterocyclic antibiotics to cancer cells.

The effect of retinoic acid on regeneration of two species of asexual planarian races, Girardia tigrina and Schmidtea mediterranea, was studied. It was established that retinoic acids at physiological concentrations (10(-7)-10(-10) M) inhibit the regeneration of the head part of planarians but have no effect on tail blastema growth. It is shown that regeneration of the head part is inhibited as a result of arrest of the cell cycle of neoblasts, proliferating stem cells, during the transition from the G1/G0 to the S phase. Thus, the morphogenetic role of retinoic acids in planarians, primitive bilaterally symmetrical animals, has been demonstrated.

Functional, biochemical and morphological studies of rat cardiac muscle after single injection of adriamycin (2.2 mg/kg) were carried out. The myocardium was taken for studies in 2 hours and in 2-3 weeks after adriamycin injection. The isolated heart was perfused retrogradely with Krebs solution and left ventricular isovolumic pressure and perfusion pressure were continuously monitored. Two-fold increase in perfusion rate was accompanied by raised developed pressure, heart rate and perfusion pressure which in the given conditions reflected a tone of coronary vessels. The cardiac contractile function of rats that received adriamycin 2 hours before, remained unaltered as compared to control group, however, perfusion pressure was raised by 26%. These hearts responded to H2O2 introduction (100 microM) into coronary vessels by more profound fall in developed pressure, which fell to 31 +/- 8% after 40 minutes vs. 61 +/- 5% in the control group (p<0.01). In two-three weeks after adriamycin injection, both cardiac contractile function and its responsiveness to oxidative stress induced by H2O2 introduction did not differ from the control, however, perfusion pressure remained elevated and this was accompanied by slowed myocardial relaxation. The myocardial concentration of malonic dialdehyde was moderately increased in adriamycin-treated group in both terms while the activity of antioxidant enzymes (SOD, GPHx and catalase) remained unaltered. Results showed an absence of the direct connection between myocardial antioxidant status and the contractile function changes at adriamycin action.

The relationship between the levels of 70 kDa family heat shock protein (Hsp) synthesis and lymphocyte sensitivity to stressors was investigated. Lymphocyte cultivation in mitogen deprived culture medium and (or) the cell treatment with alkylating agents have been used as a stress challenge. On the model of two inbred murine strains genetically contrasting by the sensitivity to alkylating agents we succeeded in demonstration that the basic level of Hsp synthesis depends on genotype. The quantity Hsp mRNA, as well as the intracellular level of the proteins were significantly higher in BALB/c than in C57BL/6 mice. The mice characterized by higher Hsp levels demonstrated higher resistance to alkylating agent action. The induction of surplus amount of Hsp by heat shock increased the cell resistance to the alkylating agent melphalan. Lymphocyte isolated from high Hsp producers, BALB/c mice, were more resistant to apoptotic signals induced by mitogen deprivation.

The effect of L-lysine-alpha-oxidase from a representative of the Trichoderma genus on the humoral immune response to protein antigens was studied. It was shown that repeated fife-fold intravenous administrations of L-lysine-alpha-oxidase in a dose of 35 U/kg had no depressive action on the humoral immunity. The enzyme had no suppressive effect on the delayed type hypersensitivity to xenogenous erythrocytes. The use of L-lysine-alpha-oxidase in a therapeutic dose or in a twice as higher dose had no reliable effect on the leukocyte migration capacity vs. the control.

The experimental data concerning the influence of repeated administration of cyclophosphamide in a total dose of 200 mg/kg on the glutathione metabolism and lipid peroxidation in the liver and kidneys of albino noninbred rats are presented. The possibility of the natural cytoprotection system correction by the use of cycloflavin was shown. The cytoprotection action mechanisms of the pharmacological agent are discussed.

Tentative results of LAK-cell and whole-body hyperthermia (WBH) were evaluated in 19 children with advanced chemorefractory tumors. LAK-cells were obtained by extracorporeal incubation of peripheral blood lymphocytes: a germ-cell rhabdomyosarcoma was detected in 4, Askin's tumor--2--2, renal cell carcinoma--2 and miscellaneous--7. Autologous LAK-cells were infused twice: on completion of WBH as body temperature fell to as low as (+) 40 deg. C and on day after WBH. The latter was well tolerated. Complete or partial response to thermochemobiotherapy was reported in 8 patients. Overall 5-year survival was 43% (median follow-up--12.6 months).

At present, choice of treatment for skin melanoma depends on empirical data on efficacy of medication. Individual treatment may be promoted if certain markers of sensitivity to chemotherapy are evaluated. We studied frequencies of expression of marker sensitivity to fluoropyrimidin [(FPd) (-1)], TS(-)0 and TS(-). TS(-/+) was reported in 36.1%. Sensitivity to platinum drugs [EPCC1(-) - 64.4%], taxotere drugs- [beta = tubulin(-) -72.7%], cyclooxygenase inhibitors [COX2(+)] - 8.9%, mutant tyrosokinase inhibitors [c = kit(+)] - 21.4%, PDGFR = beta(+) -35.5%. Marker expression in tumor tissue was heterogenous. Data on molecular-genetic characteristics of tumor may be used to individualize choice of drugs, dosage and to lower risk of toxicity. Use of cytostatics should be evaluated in clinic for their efficacy in skin melanoma with due consideration of prognostic markers.