Dependence of synergism of the combined effect of cisplatin and hyperthermia on the concentration of the drug]

The analysis of synergistic interaction of cisplatin of various concentrations and high temperature on Chinese hamster fibroblasts was performed using a mathematical model. To calculate the synergistic interaction some survival curves obtained after separate and simultaneous combined actions of these agents reported elsewhere have been used. A good agreement between experimental data and the mathematical model prognosis was provided. For a constant temperature, synergism was observed only within a certain range of cisplatin concentration. The highest value of synergism was shifted towards a lower concentration with a decrease in the temperature, at which the combined treatment was carried out. Possible practical utilization of this rule in radiation therapy, medical and food sterilization, and ecology are discussed.     

The limit of the modifiability of cellular radiosensitivity in sequential exposure to ionizing radiation and physical factors of a nonionizing nature

The application of a mathematical model of synergism in describing the consecutive combined actions of ionizing radiation and other physical agents has been considered. Using various cell systems it has been shown that the model permits to predict the highest dose modifying factor and conditions in which it can be achieved.     

Mathematical model of a simultaneous combined effect of ionizing radiation and hyperthermia

A mathematical model has been proposed suggesting that the synergistic action of a combination of ionizing radiation and hyperthermia is conditioned by additional lethal damages arising from the interaction of "sub-lesions" induced by both agents. The model describes quantitatively the synergism of the combined action of the agents used and predicts the maximal value of the synergistic effect and conditions in which it can be achieved.     

An in silico erythropoiesis model rationalizing synergism between stem cell factor and erythropoietin

Stem cell factor (SCF) and erythropoietin (EPO) are two most recognized growth factors that play in concert to control in vitro erythropoiesis. However, exact mechanisms underlying the interplay of these growth factors in vitro remain unclear. We developed a mathematical model to study co-signaling effects of SCF and EPO utilizing the ERK1/2 and GATA-1 pathways (activated by SCF and EPO) that drive the proliferation and differentiation of erythroid progenitors. The model was simplified and formulated based on three key features: synergistic contribution of SCF and EPO on ERK1/2 activation, positive feedback effects on proliferation and differentiation, and cross-inhibition effects of activated ERK1/2 and GATA-1. The model characteristics were developed to correspond with biological observations made known thus far. Our simulation suggested that activated GATA-1 has a more dominant cross-inhibition effect and stronger positive feedback response on differentiation than the proliferation pathway, while SCF contributed more to the activation of ERK1/2 than EPO. A sensitivity analysis performed to gauge the dynamics of the system was able to identify the most sensitive model parameters and illustrated a contribution of transient activity in EPO ligand to growth factor synergism. Based on theoretical arguments, we have successfully developed a model that can simulate growth factor synergism observed in vitro for erythropoiesis. This hypothesized model can be applied to further computational studies in biological systems where synergistic effects of two ligands are seen.     

Reliable predictive computational toxicology methods for mixture toxicity: toward the development of innovative integrated models for environmental risk assessment

A main objective in the field of mixture toxicity is to determine how well combined effects are predictable based on the known effects of mixture constituents. Conducting toxicity tests for all conceivable combinations of chemicals, to understand all mechanisms in the combined toxicity of environmental pollutants, is virtually unfeasible due to cost- and time-consuming procedures. Therefore, predictive tools for mixture toxicity are required to be developed within the applicable range of predictive toxicology. The concept of concentration addition (CA) model is often considered a general method for estimating mixture toxicity at the regulatory level. In the long run, however, the possibility of toxicological synergism between mixture components actually occurs, especially from the no-effect level or non-toxic substances. This is ignored under the CA concept, and needs to be examined and integrated into existing addition models at a scientific level, this paper reviews existing integrated models for estimating the toxicity of complex mixtures in literature. Current approaches to assess mixture toxicity and the need for new research concepts to overcome challenges which recent studies have confronted are discussed, particularly those involved in computational approaches to predict mixture toxicity in an environment risk assessment based on mixture components.     

Antitumor efficacy of combined gene and radiotherapy in animals

Antitumor efficacy of the combined suicide gene therapy and radiotherapy was studied on the model of CT26 murine colon adenocarcinoma. CMV-FCU1-IRES-mGM-CSF-pGL3 construct with PEG-PEI-TAT (FCU1–mGM/5-FC) block copolymer as a vector was used for intratumoral administration. Tumors were irradiated with a single 5 Gy dose. The efficacy was evaluated according to the grade of tumor growth inhibition (T/C) and lifespan of the animals. Pronounced antitumor activity of the combined use of FCU1–mGM/5-FC system with radiotherapy on the background of prolonged lifespan and the synergism of the applied methods was revealed.     

Complete starch hydrolysis by the synergistic action of amylase and glucoamylase: impact of calcium ions

Starch hydrolysis was performed by the synergistic action of amylase and glucoamylase. For that purpose glucoamylase (Dextrozyme) and two amylases (Liquozyme and Termamyl) in different combinations were investigated. Experiments were carried out in the repetitive- and fed-batch modes at 65 °C and pH 5.5 with and without the addition of Ca²⁺ ions. 100 % conversion of starch to glucose was achieved in batch experiments. Calcium ions significantly enhanced stability of the amylase Termamyl. The intensity of synergism between amylase Termamyl and glucoamylase Dextrozyme was higher than in the experiments carried out with amylase Liquozyme and Dextrozyme. Mathematical model of the complete reaction system was developed. Using the model, a possible explanation of the synergism between the amylase and glucoamylase was provided.     

Chiral stationary phases in concert with homologous chiral mobile phase additives: Push/pull model

A new “push/pull” model has been developed to explain synergistic effects observed in a system in which a chiral stationary phase (CSP) is used in combination with its homologous chiral mobile phase additive (CMPA). The model predicts the beneficial CMPA enantiomer and the counterproductive CMPA enantiomer a priori. Thus, an (R)-CSP will obtain positive synergism from a homologous (S)-CMPA and negative synergism from a homologous (R)-CMPA. The reverse is true for an (S)-CSP. The importance of structural homology between the CSP and the CMPA is demonstrated. Furthermore, the analysis time is decreased relative to the use of a CSP alone, because the retention time of the analyte peaks decreases when the CMPAs are used. © 1993 Wiley-Liss, Inc.     

Production of cellulase on sugar cane bagasse by fungal mixed culture solid substrate fermentation

Trichoderma reesei LM-UC4 and its mutant LM-UC4E1 were co-cultured with Aspergillus phoenicis QM329 for cellu-lase production on bagasse by mixed culture solid substrate fermentation. A mutual synergism was observed between the parent Trichoderma strain and the Aspergillus, resulting in enhanced combined biomass production and corresponding increased in cellulase, endoglucanase and b-glucosidase activities. Such synergism was absent with the mutant Trichoderma strain suggesting that in the hypermutation the ability for cooperative interaction with other microbes was lost.     

Potent synergistic inhibition of herpes simplex virus-2 by 9-[(1, 3-dihydroxy-2-propoxy)methyl]guanine in combination with recombinant interferons

DHPG, an acyclic guanine nucleoside with the structure 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine], showed potent synergism with recombinant alpha or beta interferons and modest synergism with gamma interferon in inhibiting the replication of herpes simplex virus type 2 in vitro. The most potent direct anti-herpes viral synergism was obtained by combination of DHPG and recombinant human interferon-beta-ser17; when combined, doses of each near their separate effective dose50's resulted in almost complete elimination of production of infectious virus within a single viral replication cycle. The anti-herpes viral activity of DHPG-interferon combinations was significantly greater than that obtained with acyclovir-interferon combinations.     

The possibilities of sensitized photomutagenesis for the induction of genetic variability in plants

It was found that combined influence of sensitizers and laser emission on vegetation under some conditions induces marked mutagenesis. The observed synergism was analysed. The possible mechanisms of the phenomenon was considered. A unified approach was proposed to assess efficacy of sensitizer-laser pairs by fragmentation DNA. The recommendations were given for application of combined action of sensitizers and laser emission for experimental mutagenesis.     

Modification of the radiosensitivity of bacteria by glutaraldehyde

A study was made of the combined effect of ionizing radiation and various concentrations of glutaric aldehyde (0.00125, 0.0025, 0.5, and 1 per cent) on viability of bacteria differing in a cell wall structure, radiosensitivity, and activity of DNA repair system. The combined effect of the two factors was shown to produce an effect of superadditive enhancement of bacterial cell death. The synergism was more pronounced in highly radiosensitive bacteria.     

Functional morphology of suprachiasmatic nuclei neurons of rat hypothalamus after the combined influence of x-irradiation and light exposure

For estimation of light radiomodification and cellular neuroadaptation of the circadian pacemarker, the morphological changes of suprachiasmatic nuclei (SCN) neurons of rat hypothalamus after 48-hours bright light exposure, the single 5 Gy whole-body X-irradiation and their combination were subjected to analysis. The dynamics of reactive and reparative changes has got a phasic character. Temporary desynchronous changes were developed in the course of the early period. Age morphological changes after X-ray and combined irradiation were discovered in the remote period. The plastic diapason of ventrolateral division (SCNv) is more considerable in comparison with dorsomedial division (SCNd). The synergism of X-irradiation and light exposure was discovered in SCNd.     

History, principles of construction of combined vaccine and problems of vaccine prophylaxis with their use

This problem article deals with modern trends in the creation and use of combined vaccines, the advantage and drawbacks of multicomponent preparations. The data on competition, interference and synergism in the action of individual components making up combined vaccines, on the cellular and molecular mechanisms of the interaction of antigens are presented. Specific features of the development of immunity induced by complex vaccines with due regard to the action of genetic and phenotypic signs, as well as the formation of humoral and cell-mediated immunity. The priority of Russian researchers in the development of the first combined vaccines is pointed out. On the basis of theoretical knowledge and accumulated practical experience the main principles of the construction and properties of combined vaccines have been formulated.