Development of systems of medicines with sustained action on the basis of biodegradable polymers is a promising trend in modem pharmacology. Polyhydroxyalkanoates (POA) attract increasing attention due to their biodegradability and high biocompatibility, which make them suitable for development of novel drug dosage forms. We obtained microspheres on the basis of poly(3-hydroxybutyrate) (PHB) loaded with the antitumor drug paclitaxel. Morphology, drug release kinetics and effect on tumor cells in vitro of microspheres were studied. The data on the kinetics of drug release, biocompatibility and biological activity of the biopolymer microspheres in vitro showed that the studied system of prolonged drug release had lower toxicity and higher efficiency compared to the traditional dosage forms of paclitaxel.

The drug composition based on the plant phospholipids and the antitumor drug doxorubicin (particle size <30 nm) was obtained using original technology elaborated in the Institute of Biomedical Chemistry (Russian Academy of Medical Sciences). In in vitro experiments demonstrated decreased drug association with blood cells for this nanophospholipid form as compared with free doxorubicin. This was accompanied by a with corresponding increase in its plasma level ans also by drug redistribution from plasma protein fraction to high density lipoproteins. Significance of these changes for doxorubicin biodistributon and antitumor activity is discussed.

The applicability of alkaline comet assay to studying the organ specificity of the genotoxic effects of drugs has been estimated using cells from four organs of mice (the liver, lungs, spleen, and brain). It has been found that cyclophosphamide damages DNA in all the four organs; and dioxidine, in all organs except the brain. It is concluded that this method can be used for studying the organ specificity of the DNA-damaging effects of various substances.

Effectiveness and safety of regional chemoinfusion in combination with radiation therapy in patients with breast cancer with metastases to the brain was clinically assessed. Cerebral angiography with chemoinfusion was fulfilled in six patients. The procedure could not be fulfilled completely in one patient because of transient vascular and neurological disorders. In the other five patients the regional superselective chemoinfusion was fulfilled successfully to the arteries feeding the metastatic foci in the brain with Carmustin in dosage 100 mg in combination with radiation therapy that was fulfilled in all six patients before the planned total focal dose. The incomplete response (n=5) to the treatment and stabilization of the process (n=l) were noted in six observations.

Despite its side-effects, most of which are reversible, effectiveness of hormonal therapy in prostate cancer has been demonstrated. Advantages of intermittent hormonal therapy have been evaluated in a number of phase II clinical tests. As a result, side-effects were shown to decrease and quality of life improved. Preliminary phase III tests failed to detect any negative effect of intermittent hormonal therapy on tumor progression-free survival as compared with continuous hormonal therapy.

Efficiency of gemcitabine plus lomustine treatment of transplantable lymphosarcoma LIO-1 in mice was significantly higher than that of monotherapy. According to the area under the kinetic curve for tumor growth, antitumor action, for single maximum tolerable dose of gemcitabine 25 mg/kg body, rose 4.6 times (p < or = 0.001), for lomustine 50 mg/kg body,--2.9 times (p < or = 0.01). The combination involved moderately increased toxicity. Lethality rate for gemcitabine+lomustine, 50 mg/kg body each, was as low as one and a half times as compared with gemcitabine therapy alone, 50 mg/kg body, (30 and 20%, respectively). The antitumor action of the combination (50 mg/kg body), was 32 times that of gemcitabine 50 mg/kg body (p < or = 0.001) and lomustine 50 mg/kg body--30 times (p < or = 0.001).

An experimental model of solid tumor of Ehrlich failed to reveal any influence of the hepatoprotector Metrop GP on tumor growth or affect antitumor action of doxorubicin.

While the most frequent, surgery for colorectal cancer is avoided in patients with metastases to the regional lymph nodes (stage III) or distant ones (stage IV). Hence, it is being increasingly substituted with neoadjuvant treatment. Our investigation is concerned with prospective evaluation of the efficacy and toxicity profile of capecitabine (XELODA) in combination with oxaliplatin (XELOX) and adjuvant Mayo treatment (stage IIb-III). Patients had undergone radical surgery (somatic status < or = 2-ECOG). The prospective group (166) received 8 courses of adjuvant polychemotherapy (XELOX); the retrospective (2001-2005) one (152)--6 (Mayo). The groups matched one another as far as number, gender, age and primary tumor localization are concerned. Regional lymph node involvement in group 1 was 64.5%; group 2--59.8%. Lympho-vascular invasion by tumor was typical of group 1; gastrointestinal toxicity - 9.2% (Mayo) vs. 7.2% in group 1. Hematological complications were 5.4% (XELOX) and 5.3% (Mayo); neutropenia-- 5.0% (Mayo) and 3.0% (XELOX); polyneutropenia-- 3.6% (XELOX); capecitabine-related Papillon-Lefevre syndrome-- 8.4%. Three-year relapse-free survival was 53.0% (XELOX) and 47.5 % (Mayo). After adjuvant treatment, toxicity profile with XELOX was lower than that after Mayo, with the survival tending to improve.

Neoadjuvant treatment should not be given to grave cases of rectal cancer with concomitant perifocal inflammation, anemia and advanced age. To improve results, intraoperative intrapelvic chemotherapy in combination with hyperthermia was carried out at the Center's Clinic. Pre-clinical studies involved working out optimal cryo-temporal regimens to maximize cytotoxic effects of drugs and hyperthermia as well as establishing systemic influence of local hyperthermia and chemotherapy on the intraoperative intrapelvic one. Our optimal cryo-temporal regimens and intraoperative intrapelvic chemotherapy proved highly effective.

Effect of the tretionine (retinoid) and aluminum chloride (neurotoxin) on the growth and differentiation of neuroblastoma cells in culture after their introduction into the medium separately and in combination was studied. The introduction of these substances creates a new information field in the medium, which becomes apparent by the reactions of neuroblastoma found on the populational and cellular levels of its organization. The presence of tretionine stimulates proliferation and induces differentiation of the cells into astrocytes. Aluminum chloride inhibits cell proliferation and enhances the process of their destruction in the monolayer. The variety of the reactions of neuroblastoma cells to the presence of these substances in the medium indicates the existence and functioning of a mechanism that selects from the information introduced only the portion which may contribute to adaptation of neuroblastoma cells to the changed culture conditions.

The report discusses our experimental data in support of biotherapy which uses chemotherapy and antitumor immune treatment with in vivo xenogenic transfer-factor polypeptides (TFP) isolated from lymphocytes sensitized to antigens of given tumor. After excision of primary tumor--lung carcinoma of Lewis--mice C57BL/6 were injected intraperitoneally with xenogenic TFP (200 pg/body, twice) and a cytostaic dose of cyclophosphamide. Such adjuvant chemotherapy was found to prevent metastases from spreading to the lung in 100%. The marked anti-metastatic effect of the treatment correlated with recovery of splenic cell mass and its cellular structure, higher levels of large granular lymphocytes in peripheral blood and enhanced functional activity of cytotoxic cells in vitro. Our results point to a possibility of raising efficacy of treating solid malignancies with adjuvant chemotherapy in combination with adoptive immune therapy.

Alloferon-1 (AF) and allostatin-1 (AS) cytotoxic and growth modulating activities have been compared. AF is cationic oligopeptide isolated from the hemolymph of experimentally infected blow fly Calliphora vicina. AS is AF synthetic analog that differs from the parent molecule in two amino acids substituted. It has been shown that both AF and AS have no direct cytotoxic activity in concentrations ranging from 1 x 10(-1) to 10 microg/ml, however, the peptides demonstrated significant effect on tumor cells proliferation in vitro. Both peptides displayed growth modulating activity in mass cell cultures and boosted growth inhibiting activity of doxorubicin in the course of P388D1 cells cloning, although AS potentated doxorubicin cytostatic activity to a greater extent. Similarly, AS boosted anti-clonogenic activity of cyclophosphamide applied in a subthreshold concentration. Experiments with peptide-fluorescein complex have demonstrated that AF and AS belong to the group of cell-penetrating peptides. Moreover, the experiments displayed AF ability to bind with chromosomes.

The detoxifying efficacy of remaxol in the experimental model of cisplatin-induced toxicosis has been studied and the possibility of using this drug in cancer patients therapy is evaluated. Remaxol exhibited pronounced dose-dependent detoxifying effect in the model of toxicosis induced by cisplatin in a toxic dose (LD50). It reduced the death rate in test animals about three times when used at a 130 ml/kg dose, and prevented lethal outcome at a 500 ml/kg dose. Remaxol also normalized biochemical blood indices that characterized liver and kidney functions in survived animals. Remaxol did not stimulate growth of experimental carcinoma, sarcoma, melanoma, and lympholeukosis. The drug did not interfere with the anti-tumor efficacy of cisplatin in the schemes with combined treatment of animals bearing tumors of various histogenesis. Remaxol can be recommended for clinical study as a detoxifying preparation for cancer patients with various malignancies.

Paclitaxel-loaded poly(lactic-glycolic) copolymer nanoparticles have been prepared using a precipitation technique. The cytotoxic activity of nanosomal paclitaxel was studied on the model of highly resistant cell line Jurkat WT (human T-cell leukemia) using various biochemical assays. It is found that the inhibitory concentration (IC50) for the experimental formulation of paclitaxel falls within 10(-4)-10(-6) M. Accumulation of nanoparticles in the highly resistant Jurkat/WT cells was revealed by fluorescence microscopy.

The effects of the new chemical substance BIV-30 on bone marrow hemopoiesis has been studied in laboratory mices on the background of myelosupression induced by a single intraperitoneal injection of cyclophosphan in a dose 160 mg/kg. The injection of BIV-30 significantly accelerated lymphocyte, monocyte, granulocyte regeneration branches of bone-marrow hemopoiesis. These results showed evidence of the hemostimulating activity of BIV-30 on the model of bone-marrow hemopoiesis deficiency.

Part 2 of this review concerns the application of melatonin (Mt) to the treatment of aged patients with cardiovascular diseases and other pathology with reference to its genoprotective and anticarcinogenic action. Effects of Mt on the cardiovascular system are underlain by its antioxidative, vasodilating, and sedative activities, the ability to regulate the heart rate and inhibit platelet aggregation. Certain authors report negative correlation between Mt production and blood cholesterol level. Mt was shown to protect from cardiac lesions associated with ischemia and reperfusion. Mt inhibits carcinogenesis and is active at systemic, tissue, cellular and subcellular levels. At the systemic level, Mt decreases hormonal production, stimulates immune activity, and prevents the development of metabolic syndrome. It inhibits cell proliferation and promotes apoptosis of tumour cells but suppresses it the nervous tissue. Mt activates telomerase. It decreases expression of oncogens and interferes with the action of mutagens and clastogens at the genetic level. Extensive studies of Mt protective action in nervous diseases are underway with special reference to spinal cord, brain, neuron and glial cell lesions; experimental cerebral stroke, Parkinson's and Alzheimer's diseases. Similar studies concern the role of Mt in the protection against ionizing radiation, the development of renal pathology, and ophthalmology (glaucoma, cataract). Mt is shown to influence practically all organ systems by inhibiting mutagenesis and maintaining correlation between circadian rhythms of different biological processes throughout human evolution.