Search

The effects of antiserotonin preparation on the development of the connective tissue in the lungs, reaction of the blood system, and the content of hemopoietic stem cells, committed hemopoietic and stromal precursors in BM, spleen, and peripheral blood were studied on C57Bl/6 mice with experimental toxic lung fibrosis caused by intratracheal administration of bleomycin. It was demonstrated that the antiserotonin drug inhibits the growth of the connective tissue in the lungs and attenuates the course inflammatory process primarily due to inhibition of the granulocytic lineage, which was related to suppression of hemopoietic stem cells. Reduced content of the stromal precursor cells in BM and spleen was noted.

The influence of granulocyte colony-stimulating factor (G-CSF) has been studied on a model of bleomycin-induced pulmonary fibrosis. It is established that G-CSF significantly increases infiltration of alveolar and alveolar duct interstitium by inflammation cells (lymphocytes, neutrophils, plasmocytes) and increases collagen deposition in lung under conditions of bleomycin introduction. Simultaneously with profibrotic and anti-inflammation effects, G-CSF increased the content of granulocyte cells in the bone marrow and peripheral blood, which was related to the stimulation of committed granulocyte precursors in the bone marrow.

In vitro experiments demonstrated increased colony-forming capacity of erythroid, granulomonocytic, and mesenchymal progenitors of the bone marrow and parenchymal progenitor elements of the liver after treatment with immobilized hyaluronidase. Increased sensitivity of these progenitor cells to erythropoietin, granulocyte colony-stimulating factor, fibroblast growth factor, and stem cell factor, respectively, was demonstrated. Immobilized hyaluronidase enhanced the formation of tissue-specific hepatic CFU against the background of reduced yield of stromal precursors in liver tissue culture containing insulin.

We studied myelotoxic effects of adriablastin and taxotere combination on granulocytic lineage cells and processes of their recovery in patients with stage III-IV breast cancer. Intensive maturation of granulocytic CFU provided regeneration of the hemopoiesis even under conditions of reduced proliferative activity of these cells, which, in turn, led to accumulation of mature and immature neutrophilic granulocytes in the bone marrow and improved reserve capacities of the neutrophil pool in the bone marrow.

In experiments designed to study effect of taxan-containing agents on the progeny of Wistar rats, one of the parents was given a single intravenous injection of the antineoplastic drug paclitaxel 1, 3 and 6 months before crossing with the untreated partner. The number of systemic pathological changes in the off-springs of paclitaxel-treated females was significantly greater and their spectrum wider than in those of the treated males. Severity of toxic effects depended on the time of crossing after drug administration. The optimal time for obtaining less affected off-springs of treated females and males was 3 and 6 months after administration of paclitaxel.

We examined the offspring of female rats that were mated with intact males in the delayed period after administration of cytostatic drugs Farmorubicin, platidiam, carboplatin, etoposide, and paclitaxel (1, 3, and 6 months post-treatment). Toxicity of these drugs in the offspring decreased in the following order: paclitaxel > etoposide > carboplatin > platidiam > Farmorubicin. The toxic effect depended not only on the type of cytostatic treatment, but also on the period of conception.

The mechanisms of granulocytopoiesis stimulation with granulocytic CSF (neupogen), added to chemotherapy protocol (adriablastine+taxotere) in patients with stages III-IV breast cancer, were studied. The hemostimulatory effect of granulocytic CSF preparation is based on stimulation of proliferation and differentiation of granulomonocytopoisis precursor cell in the hemopoietic tissue, due to neupogen effects on hemopoietic elements and on the hemopoiesis-inducing microenvironment cells.

Intraperitoneal injection of paclitaxel (Mitotax) in a single dose of 40 mg/kg was followed by an increase in the number of mitotic granulocytic and erythroid cells, hypoplasia, and pancytopenia of the bone marrow in CBA/CaLac mice. The test preparation decreased the number of hematopoietic precursor cells for erythropoiesis and granulocytopoiesis, but increased the count of polyploid cells and incidence of structural and genomic abnormalities in bone marrow cells. These changes were reversible.

Single intravenous injection of paclitaxel to rats in a maximum tolerated dose of 4.6 mg/kg was accompanied by permanent structural and functional changes in the liver. The observed changes were typical of nonspecific reactive hepatitis: infiltration with lymphocytes and macrophages, pyknosis, and focal fatty degeneration of hepatocytes. Liver enzyme activity increased in blood plasma.

The possibility of reducing the ovariotoxicity of antitumor drug etoposide with buserelin, a hypothalamic regulator of pituitary function, was studied in female Wistar rats. Quantitative analysis of ovarian structural and functional elements on serial sections through the entire organ showed that 3 months after combined treatment with etoposide and buserelin, the morphological picture of the ovarian glands did not differ from that in intact animals of the same age, while etoposide monotherapy led to earlier development of atrophic processes. Six months after treatment, the number of bi- and multilayer follicles was significantly higher in rats receiving combined therapy compared to animals treated with etoposide alone.

Progeny of Wistar rats treated with vepesid 1, 3, and 6 months before mating is characterized by common pathological changes. These changes were more pronounced and more diverse in animals descending from females receiving the cytostatic compared to the progeny of treated males. The severity of toxic effects depended on the period between mating and vepesid treatment. Cytostatic treatment 3 months before mating was associated with minimum toxicity for the progeny.

Morphological and functional state of the ovaries in female Wistar rats was assessed in the early and late periods after administration of antitumor drug vepesid in a single maximum tolerated dose. In the early period, the drug pronouncedly decreased the number of primordial follicles, bi- and multilayer follicles, and the total number of generative elements. The number of graafian vesicles and corpora lutea did not decrease. In the late period, exhaustion of the reserved potencies of gonads was more pronounced than in the control. Morphological alterations in the ovaries were accompanied by inhibition of the functional state of the female reproductive system in the period corresponding to the action on mature and primordial follicles. This inhibition manifested in increased postimplantation mortality.

We compared the function of hemopoietic stem cells under conditions of cytostatic myelosuppression (cyclophosphamide treatment) and during treatment with granulocytopoiesis stimulators. It was found that unipotent hemopoietic precursor cells are most sensitive to cyclophosphamide. Different effects of hemostimulators on stem cells are determined by different proportions between proliferation and differentiation processes.

We studied toxic effects of various schemes of cytostatic treatment on central and peripheral pools of hemopoietic precursor cells in patients with III-IV stages of lung cancer and breast cancer. It was found that erythro- and granulomonocytopoietic precursors are characterized by high resistance to cytostatic treatment compared to morphologically discernible bone marrow elements, which is probably a evolutionary developed property of this cell type aimed at rapid recovery of the hemopoietic tissue.

Experiments on adult rats showed that a single intravenous injection of antitumor drug vepeside in a MTD (maximum tolerable dose) reduced the reproductive status during periods corresponding to exposure of mature sex cells, spermatocytes, and spermatogonia in male rats and exposure of oocytes in ovulating, mature, and primordial follicles in female rats. Reduction of the male and female reproductive function manifested in increased antenatal mortality of the progeny. The toxic effects of the drug on mature male sex cells caused temporary partial infertility.

Wistar rat pups from rats treated with first- and second-generation platinum-containing cytostatics (platidiam, carboplatin) 1, 3, and 6 months before mating with intact partners had similar disorders. The severity of these disorders depended in many cases on the chemical structure of the drug and sex of the parent treated with the cytostatic. The severity of toxic effects in the progeny of intact females mated with cytostatic-treated males decreased with prolongation of the period elapsing between the treatment and mating. Carboplatin produced a more potent toxic effect on the reproductive function of rats compared to platidiam.

The structure, metabolic status, and functional properties of erythrocytes in patients with stage III-IV head and neck tumors in the course of antineoplastic cytostatic chemotherapy (platidiam, 5-fluorouracil, methotrexate) were studied. In the course of this treatment, disorders of the morphology and functional state of erythrocytes (reduced dry mass, decreased content of sulfohydryl grups and lipoproteins, increased number of transformed cells and the cells with violated ultrastructure, enhanced reversible aggregation of erythrocytes) were retained or became more pronounced.

Serum activity of tartrate-resistant acid phosphatase 5b (TRAP 5b) in patients with breast cancer and prostate cancer having bone metastases was much higher than in healthy donors and patients without skeletal injuries. TRAP 5b activity in patients with breast cancer and multiple bone metastases surpassed that in patients with single bone metastases. The mean activity of TRAP 5b and range of enzyme activity in women treated with bisphosphonates were significantly lower than in patients not receiving antiresorptive therapy. Diagnostic sensitivity and specificity of TRAP 5b as a marker of skeletal metastases in patients with breast cancer were 82 and 87%, respectively. In patients with prostate cancer these indexes were 71 and 83.4%, respectively. Detection of this marker in tumor patients holds much promise for early diagnostics of bone metastases, estimation of the severity of skeletal metastases, and monitoring of the efficiency of bisphosphonate therapy.

Examinations of the protein composition of erythrocyte membrane in patients with cancer of the stomach, large intestine and rectum by using the method of disc-electrophoresis in polyacrylamide gel revealed the changing contents of protein fractions, which consisted in a lower share of high-molecular polypeptides with, simultaneously, higher quantity of low-molecular peptides. A comparison of the studied parameters of the protein spectrum of erythrocyte membrane as observed in patients with cancer of the stomach, on the one hand, and in patients with tumors of the large intestine and rectum, on the other hand, led to defining the reliable difference only for the content of the fraction-5 proteins.

Structural and metabolic status and function of erythrocytes were studied in patients with chronic bronchitis, chronic inflammatory diseases of the upper airways, and chronic colitis. Complex study of the peripheral component of the erythron showed that disorders in erythrocyte morphology and function (decreased erythrocyte dry weight, low concentration of sulfhydryl groups and lipoproteins, decreased content of high molecular weight polypeptides in parallel with increased content of low molecular weight proteins, increased number of transformed cells, and enhanced reversible aggregation) were nonspecific and did not depend on the location of the inflammatory process.

To study characteristics of structural-metabolic status and function of erythrocytes in patients with chronic bronchitis (CB), the examination was made of 53 CB patients (39 male and 14 female). A complex study of morphofunctional state of peripheral erythron included investigation of protein and lipid composition, microviscosity of the lipid phase of erythrocyte membrane, surface architectonics, ultrastructure, reversible aggregation of red cells, concentrations of sulfhydric groups, lipoproteins and dry cell mass in erythrocytes. CB patients were found to have prominent defects in membrane structure and metabolism of mature red cells (reduced dry mass and concentration of sulfhydric groups and lipoproteins, abnormal protein composition and lipid membrane spectrum, increased viscosity of membrane lipid bilayer), alterations of surface architectonics, shape, ultrastructure of erythrocytes. Disorders in structural-metabolic status of erythrocytes in CB patients affected their functional features, the ability for reversible aggregation, in particular. Functional disturbances of erythrocytes in CB patients aggravate the course of the disease and need correction with membrane-stabilizing and membrane-repairing drugs.

The granulocyte lineage reaction and its mechanism were studied in the bone marrow of patients with breast cancer in stage III-IV treated according to a specific CAF scheme including cropanol, an antitumor drug of the animal origin. It was found that the bone marrow cytopoiesis suppressed by the cytostatics is stimulated by cropanol on the level of committed precursors, morphologically differentiated bone marrow elements, and peripheral blood.

We compared changes in the granulocytic hemopoietic stem in patients with stage III-IV lung cancer receiving cytostatic therapy by the original CVC and standard CAM schemes. In patients treated with the CVC regimen, the granulocytic hemopoietic stem possessed more potent compensatory capacities.

We studied structural and functional organization of the bone marrow, production of hemopoietic growth factors by hemopoietic cells, and plasma colony-stimulating and erythropoietic activities in CBA/CaLac mice treated with etoposide. The effects of etoposide on cultured hemopoietic and microenvironmental cells were also evaluated. Our results indicate that hemopoietic growth factors secreted by adherent bone marrow cells play the major role in the normalization of hemopoiesis during etoposide-induced myelosuppression.

Bioactive additive mammoleptin used for the treatment of fibrocystic breast disease did not stimulate the growth of primary tumors and metastases in mice with transplanted tumors. Mammoleptin in high doses inhibited the growth of Ehrlich adenocarcinoma and metastatic spreading of solid tumors.

We compared hemopoiesis-stimulating activities of dry pantohematogen and recombinant granulocyte colony-stimulating factor under conditions of cyclophosphamide-induced myelosuppression. These preparations stimulated regeneration of bone marrow granulomonocytopoiesis by various mechanisms.

Pantohematogen stimulates hemopoiesis in mice with cyclophosphane induced bone marrow hypoplasia. The hemopoiesis recovery activated by pantohematogen is manifested by the granulocyte lineage hyperplasia in the bone marrow, rapid restoration of the polymorphonuclear leukocyte and monocyte counts in the peripheral blood, and the development of neutrophilia and monocytosis. The activation effect of pantohematogen on the bone marrow hemopoiesis is related to stimulating the precursor cell proliferation and differentiation and to increasing the functional activity of the hemopoietic microenvironment.

In study of the parameters characterizing the minimal--U0(B) and maximal--UD(B) mechanical stability of aggregates, half period of red cell spontaneous aggregation--tau (in mm), photometric signal amplitude characterizing the number of red cells taking part in aggregation--A (in mm), and in calculating the aggregation index 1a and the integral coefficient of aggregation K intensification of reversible aggregation of the peripheral red blood cells was revealed in patients with lung cancer, which grew against the background of increase in the number of modified red blood cells during application of antitumor polychemotherapy.

The lipid spectrum of erythrocyte membranes was studied by thin-layer and gas-liquid chromatography in patients with lung cancer in the process of antineoplastic cytostatic chemotherapy. The control group of examined subjects was formed of healthy volunteers. During a course of antineoplastic polychemotherapy according to the CAM scheme (cyclophosphan, adriamycin, methotrexate) disorders of the erythrocyte membrane lipid spectrum in patients with II-IV stage lung cancer remained or became still more manifest.

Reversible aggregation of the peripheral blood erythrocytes was studied in patients with stages III-IV lung cancer and patients with stages II-III tumors of the head and neck (cancer of the tongue, larynx, and buccal mucosa). The parameters examined were as follows: U0 and Ud--minimal and maximal stability of aggregates, tau---red cell aggregation half-period, A--the amplitude of photometric signal (in mm) characterizing the count of erythrocytes, Ia--aggregation index, and K--integral coefficient. The findings indicate an appreciable intensification of reversible aggregation of red cells in cancer: a significant increase of U0, Ud, A, Ia, and K and decrease of tau.

It was shown in experiments on rats that intravenous infusion of the antitumor drug vepesid in a maximum tolerated dose causes stimulation of free-radical oxidation and changes in the fractional composition of lipids and phospholipids in the hepatic tissue. Changes in the activity of aminotransferases and alkaline phosphatase in the blood were recorded.

Cytophotometric (sulfhydryl groups and lipoproteins) and interferometric (dry mass) studies of the peripheral blood erythrocytes were carried out in 94 untreated patients with tumors of different localization (lung cancer, tumors of the head and neck, gastric cancer, and cancer of the large intestine). Control group consisted of healthy volunteers. The concentrations of sulfhydryl groups, lipoproteins, and mean values of dry mass of red cells of the patients with tumors were reliably lower than those in healthy controls. The degree of changes in the studied parameters depended on the tumor localization.

Hemopoiesis was studied in 88 patients with lung cancer during antitumor chemotherapy and its combination with a dry SB extract. Administration of the plant preparation was accompanied with hemopoiesis stimulation, intensification of bone-marrow erythro- and granulocytopoiesis and increase in the content of circulating precursors of the type of erythroid and granulomonocytic colony-forming units.

Cytostatic therapy of patients with lung cancer is attended with decrease in the relative number of T-lymphocytes and their theophylline-resistant population. Patients who were given SB showed a tendency towards increase of these parameters during antitumor chemotherapy. The immunoregulation index (IRI) in this case was approximately twice the background values during the whole period of investigation. The inclusion of SB in the therapeutic complex promotes increase in the number of immunoglobulins A at a stable level of immunoglobulins G.

Scanning electron microscopy of the relief of the surface of peripheral red blood cells in patients with tumors of the head and neck (cancer of the tongue, larynx, and fundal buccal mucosa) of stages II-III and with stages III-IV lung cancer revealed similar changes, characterized by a manifest drop in the count of discocytes and increased share of transitional, prehemolytic, and degenerative forms of cells.

It has been shown in experiments on Wistar rats that the antitumor agent platidiam given in MTD causes increased activity of alanine and aspartate aminotransferases (up to the 15th day after administration), persisting changes in the beta- and pre-beta-lipoprotein level, and intensified LPO in the blood (up to 3-months). Acute toxic hepatitis induced in rats by injection of CCl4 1, 3, and 6 months after a single platidiam administration is characterized by hepatic disorders which are more pronounced than those than those in intact animals with CCl4 hepatitis.

Experiments on Wistar rats studied the state of the posterity born as a result of mating of intact females with males, who were injected with the antitumor drug platidiam one month before mating (once, intravenously, maximal tolerance dose). The pre- and postimplantation death rate did not grow in female rats mated with test males. However, the fetuses showed visceral anomalies and delayed development of skeleton. A decrease in the muscle tone, as well as ability for the training and extrapolation behavior, were observed in some newborn rat pups.

The experiments performed on Wistar rats showed morphological damages of the rat testis over a one-month period after platidiam administration (4 mg/kg, one-time intravenous injection), namely a decrease in the index of spermatogenesis, in the number of normal spermatogonia, Leydig cells, and testis tubes at the 12th stage of meiosis and an increase in the number of testis tubes squamous epithelium. In the remote period (3 and 6 month after platidiam administration) the recovery of morphological and functional state of the rat testis was observed.

The paper outlines the principles in designing hemostimulators by using glycosamineglycans. Hemostimulating properties of the tested agents is likely to be primarily due to the presence of D-glucuronic acid in their structure. The homotypic mechanisms are largely responsible for all agents' effect in stimulating hemopoiesis. Thus, they all virtually activate the function of the hemopoiesis-inducing microenvironment. In addition, they directly or indirectly stimulate the processes of proliferation and differentiation of precursor cells of erythro- and granulomonocytopoiesis.

Cisplatin and platin given in LD50 to mice caused significant changes in hepatic metabolism. There was enhanced lipid peroxidation with accumulation of malonic dialdehyde, dienic conjugates, Schiff bases, decreased antiradical activity and alterations in the fractional composition of phospholipids with higher concentrations of membranotoxic ingredients. There was also an increase in the serum activity of transaminases and alkaline phosphatase.