Cytostatic Cyclophosphamide Research Articles

Reaction of the oral mucosa to damage and its regeneration during cytostatic therapy

Objective: Experimental study of the damaging effect of cytostatics on the oral mucosa, disruption of the protective mechanisms of the mucous membrane, as well as assessment of the reversibility of these changes.
 Materials and methods: Using histological, morphometric, and quantitative histochemical methods, the mucous membrane of the tongue was studied on 40 mature white outbred mice after intraperitoneal administration of the cytostatic cyclophosphamide (CP) at a dose of 400 mg/kg for 5 days (20 animals). Animals in the control group (20 mice) were injected with isotonic sodium chloride solution at the same frequency. The material was obtained 24 hours and 20 days after the last injection of the drug. The condition of the oral mucosa (OM) on the ventral surface of the tongue was assessed.
 Results: Exposure to CP led to damage to all layers of the mucous membrane: the processes of proliferation and keratinization of the integumentary epithelium were disrupted, and synthetic processes in the epithelial cells of the small mixed salivary glands were disrupted. The number of granulocytes and mast cells decreased, and the relative volume of blood vessels in the connective tissue of the mucous membrane decreased. The changes were reversible.
 Conclusions: Cytostatic therapy leads to damage to the oral mucosa and disruption of its supraepithelial, epithelial and subepithelial protective mechanisms. There is a high degree of regeneration of the mucous membranes after the withdrawal of the cytostatic drug.

Chemotherapy's impact on a few blood parameters

Cyclophosphamide (CP), Ifosfamide (IFO), Paclitaxel (PTX) and Doxorubicin (DOX) are commonly used cytostatic drugs. The present study investigates the ecotoxicity and genotoxicity of CP, DOX, and PTX, their human metabolites/transformation products (TPs) cyclophosphamide (NCP) as individual compounds and as a mixture. The three-parent compounds ( Further ecotoxicity studies of metabolites. The measured toxicity of the cross was lower than the toxicity predicted by the concentration addition model indicating potentiating effects of the CPCOOH toxicity. Revealed genotoxic activity of CP and the mixture in the presence The degradation study with UV irradiation of samples containing (CP, cyclo, and DOX ) showed efficient degradation of compounds and remained toxic. They are suggesting that no stable with adverse effects was formed. This is the first study describing the ecotoxicity and genotoxicity of the commonly used cytostatics CP, cyclo, and DOX, their known metabolites, and their mixture. The results indicate the importance of toxicological evaluation and monitoring drug metabolites as they may be more hazardous to humans than parent compounds. Keywords. Paclitaxel. Doxorubicin. Cyclophosphamide. toxicity

Effect of Serratula marginata dry extract on the mice thymus and spleen structure in cyclophosphamide immunosuppression

BACKGROUND: The search of effective and safe drugs to prevent and treating the immune deficient states is an actual problem of modern medicine.
 AIM: The purpose of the study is to evaluate the effect of Serratula marginata dry extract on structure of mice thymus and spleen at cyclophosphamide immunosuppression.
 MATERIALS AND METHODS: The experiments were carried out on F1 (CBAxC57Bl/6) mice. Immune deficiency was simulated by a single intraperitoneal introduction of cyclophosphamide in the dose 250 mg/kg. S. marginata dry extract in the dose 100 mg/kg was administered to animals for 14 days intragastrically against cyclophosphamide. Morphological studies of the thymus and spleen were performed on day 16 after the extracts administration. Areas white and red pulp of the spleen; the area of the thymic lobule, the cortex and the medulla; the density of cells in the subcapsular zone and the deep layers of the cortex were measured using the Zen 2012 image analysis program.
 RESULTS: The S. marginata extract limited the development of involutive changes in the thymus caused by cyclophosphamide: the thymus area was by 28% (p 0.05) higher and the cortical-medullary index was (ratio of the cortex area to the medulla area) by 26% higher. The number of mitotically dividing cells, blasts and large lymphocytes increased, the number of cells with structural disorders and macrophages decreased in the thymus cortex. In animals of the experimental groups, the white pulp area was 47% (p 0.05) higher than that in the control.
 CONCLUSIONS: The S. marginata dry extract limited the development of involutive processes in the thymus and spleen caused by the introduction of cytostatic cyclophosphamide.

Effect of 3d-metal gluconates on leukocyte parameters of endogenous intoxication

Background. The development of endogenous intoxication in the treatment of oncological pathology with cytostatic drugs complicates targeted therapy, so the search for correctors of these conditions is an actual task. Previously, we have shown in vivo the corrective effect of 3d-metal gluconates on the humoral link of immunity with the administration of the widely used cytostatic cyclophosphamide. It is of interest to evaluate the effect of 3d-metal gluconates on changes in leukocyte parameters of endogenous intoxication affected by cyclophosphamide.
 Aim. Evaluation of the effect of 3d-metal gluconates (Mn, Fe, Co, Cu, Zn) on the degree of endogenous intoxication in mice against the background of the cytostatic effect of cyclophosphamide.
 Material and methods. The experiment was carried out on white laboratory male mice weighing 2528 g, divided into 9 groups [1 intact animals, 2 administration of cyclophosphamide without treatment, 3 administration of cyclophosphamide and a comparison drug with an immunostimulating effect, 4 administration of cyclophosphamide and the comparison drug calcium gluconate, groups 59 administration of cyclophosphamide and gluconates of 3d-metals (MnGl, FeGl, CoGl , CuGl and ZnGl, respectively)], 12 individuals each, kept in the vivarium conditions on a standard diet. Endogenous intoxication was induced by a single injection of cyclophosphamide. 3d-metal gluconates (Mn, Fe, Co, Cu, Zn) and comparison drugs (glucosaminylmuramyl dipeptide in the form of Likopid, and calcium gluconate) were used to correct changes in the immune system. The administration of the drugs was started 24 hours after the administration of the cytostatic and then daily orally during 21 days. Blood sampling was performed on the 22nd day. The assessment of the degree of endogenous intoxication was carried out by determining the leukocyte indices: stress activity index, leukocyte intoxication index, nuclear index of the degree of endotoxicosis, and leukocyte shift index. Statistical processing of the results was performed using the Statistica 10.0 program. To calculate the significance of differences between groups, the nonparametric MannWhitney test was used. Changes were considered significant at p 0.05.
 Results. After the administration of cyclophosphamide in animals, a significant change in the leukocyte formula, which indicates an acute intoxication of the body, was observed: there was a decrease in the content of monocytes (3 times), segmented neutrophils (1.5 times), an increase in stab neutrophils (2 times), lymphocytes (1.1 times). The intake of 3d-metal gluconates led to the correction of leukocyte indices, the degree of which statistically significantly exceeded the degree of correction by the comparison drugs Licopid and Calcium gluconate (p 0.05), and for Zn (II) gluconate it was from 45 to 84%, for Mn (II) gluconate from 44 to 100%.
 Conclusion. Gluconates of 3d-metals reduce the degree of endogenous intoxication caused by cyclophosphamide, increase the reactivity of phagocytes and the regeneration rate of the leukocyte link. In terms of efficiency, 3d-metal gluconates can be arranged in the following order (according to metals): Mn ˃Zn ˃Cu ˃Co ˃Fe.

Детоксикация корней молочая Фишера и иммуномодулирующая активность его экстракта

The object of this study was the roots of Euphorbia Fischeriana L. The presence of six marker components, such as antiquorin, en t -atisan-3b,16a,17-triol, en t -16a,17-dihydroxyatizan-3-one, cauranic acid, jolkinolide B, jolkinolide A, was established by HPLC in samples of Fischer’s milkweed. Analytically, the content of diterpenes was compared before and after extraction with various extractants (goat broth and myrobalan solution). It was found that the use of goat broth as an extractant made it possible to maximally remove resins containing anthraglycosides and alkaloids, which have a strong irritating effect on the mucous membrane of the gastrointestinal tract. Thus, the content of antiquorin decreased from 0.49 to 0.01; en t -atisan-3b,16a,17-triol from 7.23 to 0.06; en t -16a, 17-dihydroxyatizan-3-one from 0.42 to 0.02; Cauranoic acid from 0.20 to 0.01; jolkinolide B from 0.41 to 0.08, jolkinolide A from 0.22 to 0.02 mg/g, respectively. The study of the immunomodulatory properties of Fisher’s milkweed extract revealed its effectiveness in relation to the reactions of the cellular, humoral and macrophage links of the immune response in experimental immunodeficiency caused by the cytostatic cyclophosphamide. Fisher’s milkweed extract at a dose of 200 mg/kg is able to weaken the suppressive effect of cyclophosphamide on the cell-mediated immune response, antitelogenesis and phagocytosis of macrophages. 10.30906/2073-8099-2022-14-2-21-25

Downregulation of MMP-9 Enhances the Anti-Migratory Effect of Cyclophosphamide in MDA-MB-231 and MCF-7 Breast Cancer Cell Lines.

Metastasis is one of the most urgent issues in breast cancer patients. One of the factors necessary in the migration process is the remodeling of the extracellular matrix (ECM). Metalloproteinases (MMPs) can break down the elements of the ECM, which facilitates cell movement. Many highly aggressive tumors are characterized by high levels of MMPs. In the case of breast cancer, the association between MMP-9 and the migration potential and invasiveness of cells has been demonstrated. In addition, reports indicating increased migration of breast cancer cells after the administration of the commonly used cytostatic cyclophosphamide (CP) are particularly disturbing. Hence, our research aimed to assess the effect of CP treatment on MDA-MB-231 and MCF-7 cells and how this response is influenced by the downregulation of the MMP-9 level. The obtained results suggest that CP causes a decrease in the survival of breast cancer cells of various invasiveness, and the downregulation of MMP-9 enhances this effect, mainly by inducing apoptosis. Moreover, in the group of MMP-9 siRNA-transfected CP-treated cells, a more severe reduction in invasion and migration of cells of both lines was observed, as indicated by the migration and invasion transwell assays and Wound healing assay. Hence, we suggest that CP alone may not result in satisfactory therapeutic effects. On the other hand, the use of combination therapy targeting MMP-9, together with the CP, could improve the effectiveness of the treatment. Additionally, we confirmed a relationship between the levels of MMP-9 and cytokeratin 19 (CK19).

The Effect of Carbon Nanomaterials on the Toxicity Indices of Cyclophosphamide under Combined Administration

Carbon nanomaterials (CNMs) and single- and multiwalled carbon nanotubes and fullerene derivatives are considered as promising agents for the delivery of pharmacological agents to target organs in anticancer therapy and theranostics. Cytostatic cyclophosphamide (CP) is one of the chemotherapeutic drugs the targeted delivery of which is possible by CNMs. However, due to the presence of its own toxic effect in various CNMs, the question about their possible effect on the general toxic and immunotoxic effect of CP when administered together arises. The combined effect of CP and CNMs, i.e., multiwalled carbon nanotubes (MWCNTs), single-walled carbon nanotubes (SWCNTs), and polyhydroxylated fullerenol (PHF60), administered orally daily at a dose of 0.1 mg/kg of body weight, was studied in Wistar rats. In two experiments lasting 16 and 35 days with different scenarios of CP-induced immunosuppression, the lethality and integral parameters were assessed; the contents of erythrocytes and leukocytes; the biochemical parameters; the levels of cytokines, chemokines, and growth factors; and the activity of glutathione peroxidase-I of erythrocytes were studied in the blood. The concentration of selenium and the excretion of creatinine and 8-oxo-2-deoxyguanosine were studied in the urine. The level of reduced glutathione was studied in the liver homogenate. In the first experiment, the consumption of both MWCNTs and SWCNTs led to an almost twofold decrease in lethality caused by the introduction of CP. In the second experiment, a twofold decrease in the lethality was noted only for SWCNTs; nevertheless, MWCNTs and PHF60 also had a positive effect on the survival of animals. Consumption of CNMs did not have a significant effect on the biochemical parameters, the state of the erythropoiesis system, the weight of the thymus and spleen, or the levels of key regulatory molecules impaired due to CP treatment. At the same time, MWCNTs, SWCNTs, and PHF60 are able to reduce a number of manifestations of the CP immunotoxic effect, including the lethality, lymphopenia, and impaired balance of cytokines and chemokines/growth factors: IL-4, IL-13, IL-17A, IFN-γ, IL-18, GM-CSF, GRO-KC, IL-12p70, IL-1β, IL-7, TNF-α, and VEGF. Thus, MWCNTs and SWCNTs, when administered together with CP, have a paradoxical effect consisting in the partial cancellation of the disturbances caused by it, which can be explained by the known ability of CNTs to enhance the mobilization, migration, and adhesion of blood cells and to trigger immune responses.

Sulfur-containing phenolic antioxidants increasing antitumor efficiency of cyclophosphamide and its combination with nitric oxide donor

Due to the multifactorial nature of cancer diseases, investigations of combinations of the known cytostatics with substances that are chemosensitizers and act on various molecular target in the organism gain increasing significance. Polyfunctional compounds, whose molecules contain several reaction centers, serve as resources improving the efficiency of the chemosensitizing effect of various substances for chemotherapy by cytostatic agents. Classical representatives of such polyfunctional substances are sulfur-containing derivatives of alkylated phenols, the high oxidation activity of which is determined by a combination of the antiradical activity of the phenol fragments with the antiperoxide activity of the sulfur-containing groups. It is shown that the sulfur-containing phenolic antioxidant sodium S-[3-(3-tert-butyl-4-hydroxyphenyl) propyl] thiosulfate (TC-13) has no antitumor activity but enhances chemotherapeutic activity of cytostatic cyclophosphamide taken in a subtherapeutic dose, increasing the index of average life span of mice with leukemia P388 from 196 to 283%. In addition, a combination of TC-13 with the nitric oxide donor (NaNO2) increases the antitumor activity of cytostatic cyclophosphamide by 110% for the same experimental model of mice at 50% survived animals.

Морфометрична характеристика слизової оболонки порожнини рота і зміна показників гуморального імунітету при впливі різних типів запальної реакції за умови експериментального гастродуоденіту

Introduction. Mucous membrane of the oral cavity is a sensitive indicator of evaluation of pathological processes of gastrointestinal tract, due to its morphological features difference compared with other mucous membranes. At digestive system diseases, depending on the lesion level of one organ or another, morphological changes of mucous membrane of all oral cavity parts take place and changes in immunological parameters of animal blood.The aim of the study – to examine and evaluate changes of morphometric parameters of the mucous membrane of the oral cavity of the buccal area and changes of humoral immunity under the influence of various types of inflammatory reaction at experimental gastroduodenitis.Materials and Methods. The experimental study was carried out on 42 male rats with weight 180-200 g. For all animals they modeled acute gastroduodenitis during 7 days. Hypoergic type of inflammatory reaction was modeled with intramuscular injection of alkylating cytostatic cyclophosphamide. Hyperergic type of inflammatory reaction was modeled with intramuscular injection of pyrogenal on physiological solution. Normoergic type of inflammatory reaction developed in the animals with experimental gastroduodenitis without additional injection of any substances. In order to make the experiment the animals were divided into 4 groups. The animals were withdrawn from the experiment with rapid decapitation under thiopental – with sodium anesthesia. Anatomic preparation of the oral cavity buccal area and morphometric measurements were made, using the methodology of H. H. Avtandilov. During morphometric examination they measured mucous membrane thickness, epithelial layer, lamina propria, basal membrane, specific gravity of damaged epitheliocytes of osteoid layer, relative volume of capillaries. In animals we determined the level of the concentration of Ig A, M, G in serum in a semi-automatic biochemical analyzer «Humalyzer 2000». Results processing was made at the department of system statistical research of the State Higher Educational Institution « I. Ya.HorbachevskyTernopilStateMedicalUniversity, Ministry of Public Health ofUkraine» in the software package Statsoft STATISTIKA.Results and Discussion. According to the results of the experimental study we found changes in the oral mucosa. The cause of buccal mucous membrane thinning was significant thinning of the epithelial layer, which can be explained by degenerative changes of different intensity. At the same time other structural components of mucous membrane of the buccal area of the oral cavity, namely basement membrane and lamina propria, were thickened on the contrary. The most evident dystrophic changes of the epithelium of buccal mucous membrane at microscopy were revealed in the animals with hyperergic type of inflammatory reaction. The important indicator of alteration processes in the mucous membrane of the oral cavity is specific part of damaged epitheliocytes, that 10 day study on indicators was increased relatively to control in these listed groups. Circulatory disturbance played an important role in the pathogenesis changes of mucous membrane of the oral cavity buccal area at modeled gastroduodenitis against the background of various types of inflammatory reaction. It appeared as level intensification of capillaries relative volume at morphometric investigation. In male white rats with hyperergic, normoergic, hypoergic TIR and morphometric changes in buccal areas consistent with immunological parameters. It was found that the levels of Ig A, M, G were higher relative to controls in all investigated groups of animals. The obtained results confirm that the changes of morphometric and immunological parameters depend on the type of inflammatory reaction.Conclusions. Changes of morphometric data were accompanied with thickness decrease of mucous membrane and epithelial layer, increase of thickness of the lamina propria, basement membrane, specific part of damaged epitheliocytes of osteoid layer and capillaries relative volume during 10 days of the experiment regardless of the inflammatory reaction type. Changes in humoral immunity accompanied by rising levels of Ig classes A, M and G relative control within 10 days. The most significant changes were found in animals with hyperergic type of inflammatory reaction, the least – with hypoergic type of inflammatory reaction in animals normoergic type of inflammatory reaction of change took an intermediate position.

Human metabolites and transformation products of cyclophosphamide and ifosfamide: analysis, occurrence and formation during abiotic treatments

This study describes a gas chromatography-mass spectrometry analytical method for the analysis of cytostatic cyclophosphamide (CP), ifosfamide (IF) and their selected metabolites/transformation products (TPs): carboxy-cyclophosphamide (carboxy-CP), keto-cyclophosphamide (keto-CP) and 3-dechloroethyl-ifosfamide/N-dechloroethyl-cyclophosphamide (N-decl-CP) in wastewater (WW). Keto-cyclophosphamide, CP and IF were extracted with Oasis HLB and N-decl-CP and carboxy-CP with Isolute ENV+ cartridges. Analyte derivatization was performed by silylation (metabolites/TPs) and acetylation (CP and IF). The recoveries and LOQs of the developed method were 58, 87 and 103% and 77.7, 43.7 and 6.7ngL(-1) for carboxy-CP, keto-CP and N-decl-CP, respectively. After validation, the analytical method was applied to hospital WW and influent and effluent samples of a receiving WW treatment plant. In hospital WW, levels up to 2690, 47.0, 13,200, 2100 and 178ngL(-1) were detected for CP, IF, carboxy-CP, N-decl-CP and keto-CP, respectively, while in influent and effluent samples concentrations were below LOQs. The formation of TPs during abiotic treatments was also studied. Liquid chromatography-high-resolution mass spectrometry was used to identify CP and IF TPs in ultrapure water, treated with UV and UV/H2O2. UV treatment produced four CP TPs and four IF TPs, while UV/H2O2 resulted in five CPs and four IF TPs. Besides already known TPs, three novel TPs (CP-TP138a, imino-ifosfamide and IF-TP138) have been tentatively identified. In hospital WW treated by UV/O3/H2O2, none of the target metabolites/TPs resulted above LOQs.

Ecotoxicity and genotoxicity of cyclophosphamide, ifosfamide, their metabolites/transformation products and their mixtures

Cyclophosphamide (CP) and ifosfamide (IF) are commonly used cytostatic drugs that repress cell division by interaction with DNA. The present study investigates the ecotoxicity and genotoxicity of CP, IF, their human metabolites/transformation products (TPs) carboxy-cyclophosphamide (CPCOOH), keto-cyclophosphamide (ketoCP) and N-dechloroethyl-cyclophosphamide (NdCP) as individual compounds and as mixture. The two parent compounds (CP and IF), at concentrations up to 320 mg L−1, were non-toxic towards the alga Pseudokirchneriella subcapitata and cyanobacterium Synecococcus leopoliensis. Further ecotoxicity studies of metabolites/TPs and a mixture of parent compounds and metabolites/TPs performed in cyanobacteria S. leopoliensis, showed that only CPCOOH (EC50 = 17.1 mg L−1) was toxic. The measured toxicity (EC50 = 11.5 mg L−1) of the mixture was lower from the toxicity predicted by concentration addition model (EC50 = 21.1 mg L−1) indicating potentiating effects of the CPCOOH toxicity. The SOS/umuC assay with Salmonella typhimurium revealed genotoxic activity of CP, CPCOOH and the mixture in the presence of S9 metabolic activation. Only CPCOOH was genotoxic also in the absence of metabolic activation indicating that this compound is a direct acting genotoxin. This finding is of particular importance as in the environment such compounds can directly affect DNA of non-target organisms and also explains toxicity of CPCOOH against cyanobacteria S. leopoliensis. The degradation study with UV irradiation of samples containing CP and IF showed efficient degradation of both compounds and remained non-toxic towards S. leopoliensis, suggesting that no stable TPs with adverse effects were formed. To our knowledge, this is the first study describing the ecotoxicity and genotoxicity of the commonly used cytostatics CP and IF, their known metabolites/TPs and their mixture. The results indicate the importance of toxicological evaluation and monitoring of drug metabolites as they may be for certain aquatic species more hazardous than parent compounds.

Antitumor effect of the conjugate of synthetic carbohydrate moiety of the tumor-associated ganglioside GM3 with hemocyanin in combination with the cytostatic cyclophosphamide

Based on the carbohydrate chains of tumor-associated ganglioside, polyvalent carbohydrate-protein conjugate 1 was synthesized suitable as a prototype of a cancer vaccine containing ∼400 residues of 3′-(N-acetyl-a-neuraminyl)lactose (3′-sialyllactose) per macromolecular complex of the hemocyanin protein of the Megathura crenulata keyhole limpet. The integrated antitumor effect of neoglycoconjugate 1 in combintion with the cytostatic cyclophosphamide was studied on the C57Bl/6 mice with transplanted melanoma B16/F0 cells.

Polyfunctional action of biologically active compounds in antitumor chemotherapy of cyclophosphamide

Combinations of the known cytostatic cyclophosphamide (cyclophosphan) with hydroxamic acids (asparagylhydroxamic and salicylhydroxamic), nitric oxide donor (sodium nitrate), and an original hybrid non-steroidal anti-inflammatory compound, viz., diclofenachydroxamic acid nitrate salt (DHA·HNO3), were studied. The use of cyclophosphan in combination with these substances increases the efficiency of chemotherapy and elongates the life of animals with leukemia P-388. The dynamics of changes in the signal from cytochrome P-450 in the liver samples after the administration of DHA·HNO3 to the animals was studied by ESR spectroscopy. The mechanism of the action of DHA·HNO3 enhancing the chemotherapeutic effect of cyclophosphan was proposed.

Antitumoral effects of Aconitum soongaricum tincture on Ehrlich carcinoma in mice

s. PHYTOPHARM 2012 M 34 Obzory po kliniceskoj farmacologii i lekarstvennoj terapii [Reviews of clinical pharmacology and drug therapy] ТОМ 10/2012/2 ANTITUMORAL EFFECTS OF ACONITUM SOONGARICUM TINCTURE ON EHRLICH CARCINOMA IN MICE © Alefirov A. N., Bespalov V. G. The N. N. Petrov Research Institute of oncology of the Russian Ministry of Health and Social Development, St. Petersburg, Russia The aim of the study was estimation of antitumoral activity of tincture of Aconitum soongaricum Stapf. tubers given at various doses and schemes in bAlb/c mice with Ehrlich carcinoma. Standard 10 % Aconitum soongaricum tincture (AST) contained 0.08 % of alkaloids was used. ld50 of AST was defined by a method of probit analysis. Ehrlich carcinoma (5 × 10 6 of tumor cells) was transplanted intramuscularly to 204 female mice and to 80 male mice. AST was administered intragastrically by tube at doses from ld10 to 10 % from ld10 one time or daily during from 5 till 20 days and also as a metronomic therapy at doses from 12.5 % to 50 % from ld10 daily up to the death of mice. Effects of AST were estimated on indicators of the inhibition of tumor growth (iTG) and increase of life span (ilS) compared with control groups of mice that were given intragastrically water. As a comparison drug it was used cytostatic cyclophosphamide which was given intraperitoneally at a dose 200 mg/kg of body weight. ld50 of AST in tenfold dilution for male and female mice was 17,4 ± 1,71 and 20,8 ± 1,28 ml/kg of body weight, accordingly. ld10 of AST in tenfold dilution for male and female mice was 9.7 and 16.3 ml/kg of body weight, accordingly. in female mice the most efficient inhibitions of the Ehrlich carcinoma growth were found under administrations of AST at ld10 dose daily within 5 days (maximal statistically significant iTG was 59.1 %, ilS was 9.3 %) and at a dose of 25 % from ld10 daily within 20 days (maximal statistically significant iTG was 43.3 %, ilS was 9.8 %). The metronomic therapy in female mice was the most efficient by daily administration of AST at a dose of 12.5 % from ld10 (maximal statistically significant iTG was 40.1 %, ilS was 8.8 %). in male mice the most efficient antitumoral action was found at application of AST at a dose of 25 % from ld10 daily within 20 days (maximal statistically significant iTG was 50.0 %, ilS was 20.9 %). Antitumoral effects of AST at these most effective schemes of application were comparable with antitumoral effect of cyclophosphamide. AST is perspective for clinical use as an anticancer remedy. The most efficient are short-term courses of administration of AST at maximal tolerable doses and long courses of administration of AST at doses from 12.5 % to 25 % from ld10. REPRODUCTIVE TOXICITY OF OIL EXTRACT OF SCHISANDRA CHINENSIS SEEDS © Avdeeva O. I., Makarenko I. E., Makarov V. G., Simanovskaya M. S. St-Petersburg institute of Pharmacy, Russia The aim of this study was to evaluate the reproductive toxicity of oil extract of Schisandra chinensis seeds. Generative function, embryoand fetotoxicity were tested. The oil extract was administered in two doses 50 and 1000 mg/kg per os to male rats during 60 days period and 15 days period to female rats. The results shown that the oil extract in doses 50 and 1000 mg/kg had no toxic effects on the male generative function and there was no toxic effects on reproductive function in female rats. Administration of oil extract in doses 50 and 1000 mg/kg did not lead to embryotoxic and teratogenic effects evaluated in pregnant female rats in the antenatal period. The physical state, sensory-motor reflexes and behavioral responses of rat progeny were not changed after the oil extract administration. Thus, the results of this study shown that there was no toxic effects after the administration of oil extract of Schisandra Chinensis seeds. in particular, the administration of oil extract in doses 50 and 1000 mg/kg did not affect the generative function of male rats, and did not cause the embryo and fetotoxicity observed in the antenatal and postnatal periods.

Inhibition of metastasis development by daily administration of ultralow doses of RNase A and DNase I

Recent data on the involvement of miRNA and circulating tumor-derived DNA in regulation of tumorigenesis showed a great prospect for these molecules as a novel class of therapeutic targets and gave a new start for the study of enzymes cleaving nucleic acids as potential antitumor and antimetastatic agents. In the present paper using two murine tumor models with pulmonary or liver metastases we studied the antimetastatic potential of RNase A and DNase I and performed a search for possible molecular targets of the enzymes. Herein, we show for the first time that daily administration of ultralow doses of RNase A (0.5–50 μg/kg) and DNase I (0.02–2.3 mg/kg) inhibits the development of metastasis to 60–90% and RNase A exerts 30% retardation of tumor growth. Remarkably, the increase in RNase A dose from 50 μg/kg to 10 mg/kg leads to a disappearance of antitumor and antimetastatic effects. Simultaneous treatment of tumor-bearing animals with RNase A and DNase I leads to an additive effect and results in almost total absence of metastases. The use of RNase A as an adjuvant in conjunction with conventional cytostatic cyclophosphamide results in a reliable enhancement of antitumor and antimetastatic effect of the therapy compared with the use of these agents individually. The search for possible molecular mechanism of antimetastatic effect of nucleases showed that daily administration of the enzymes reduced the pathologically increased level of extracellular nucleic acids and increased nuclease activity of the blood plasma of tumor-bearing mice back to the level of healthy animals. Thus, we unequivocally show that the proposed protocol of treatment of tumor-bearing animals with RNase A and DNase I has a general systemic and immunomodulatory effect, leads to a drastic suppression of metastasis development, and in perspective may become an effective component of intensive complex therapy of cancer.

Miltefosine decreases the cytotoxic effect of Epirubicine and Cyclophosphamide on mouse spermatogenic, thymic and bone marrow cells

A new class of potent anticancer drugs, alkylphosphocholines has been recognized lately. Miltefosine (Hexadecylphosphochlorine, HPC) has been found to express select antineoplastic effect on human breast cancer skin metastases with simultaneous preservation of bone marrow proliferative activity and low clastogenicity. In the current study, we present data about the specific effect of two widely used cytostatics Cyclophosphamide (CP) and Epirubicine (ERb) applied separately or in combination with Miltefosine. C57BL6 mice were treated per os or intraperitonieally in doses corresponding to that in clinical use. Morphological, autoradiographic, ultrastructural and cytogenetic studies on spermatogenic, thymic and bone marrow cells were performed. It is found that compared with separate application, combinations of ERb or CP with Miltefosine slightly decreases spermatogonial proliferation and exerts milder effect on the structure of germinal and thymic cells. In addition, a lot of plasmocytes showed signs of active protein (antibody) synthesis. A significant reduction of aberrant chromosomes (clastogenicity) without changes in proliferative activity of bone marrow cells were recorded. In conclusion, the combine application of Miltefosine with ERb and CP decreased the destructive cytotoxic effects of ERb and CP on mouse spermatogenic and hematopoietic cells.