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.     

Mathematical modeling of synergistic interaction of sequential thermoradiation action on mammalian cells

Data obtained by other authors for mammalian cells treated by sequential action of ionizing radiation and hyperthermia were used to estimate the dependence of synergistic enhancement ratio on the ratio of damages induced by these agents. Experimental results were described and interpreted by means of the mathematical model of synergism in accordance with which the synergism is expected to result from the additional lethal damage arising from the interaction of sublesions induced by both agents.     

Prognosis of yeast cells recovery after simultaneous exposure to UV-radiation and hyperthermia

The results of experimental investigations of survival of diploid yeast cells Saccharomyces cerevisiae (strain XS800) after simultaneous exposure to UV-radiation (254 nm) and hyperthermia (53-57 degrees C) have been described. It was shown that the portion of cells capable of recovery in innutrient medium after the action of these agents decreased with the increasing of temperature under which the irradiation was occurred. Mathematical model taking into account the synergistic interaction was suggested for quantitative prediction of irreversible component after combined actions of these agents. A good correspondence between experimental data and model predictions has been demonstrated. The importance of the results obtained for the interpretation of the synergistic interaction mechanisms are discussed.     

Dependence of synergism of the combined effect of ultrasound and hyperthermia upon intensity of ultrasound

The inactivation of wild-type yeast Saccharomyces cerevisiae was studied after simultaneous treatment with ultrasound and hyperthermia. A temperature range was established within which ultrasound and hyperthermia exert a synergistic action. The effect was shown to depend on ultrasound intensity and the temperature at which the treatment takes place. The temperature range enhancing the ultrasound effect shifted forward higher temperature with increasing ultrasound intensity. For every intensity value, an optimal temperature exists at which the synergetic effect is maximum. The biophysical interpretation of the results obtained is based on the assumption that synergism is due to an additional lethal damage, which arises from the interaction of some sub-lesions induced by both agents. These sublesions are considered non-lethal if the agents are applied separately.     

The prognosis of the portion of irreversible radiation damages after simultaneous action of hyperthermia and ionizing radiation on yeast cells

The results of experimental research of diploid yeasts cells survival after simultaneous action of hyperthermia and ionizing radiation (60Co) have been described. It was shown that the cell ability to liquid holding recovery decreased with an increase in the temperature, at which the exposure was carried out. due to the increase in the irreversible component determining the relative part of radiation damage which cells are incapable to recover. To predict theoretically the relative part of irreversible radiation damage after combined action, the mathematical model was suggested taking into account the synergistic interaction of agents. Good correlation between experimental results and model prediction was demonstrated. The importance of the results obtained for the interpretation of the mechanism of synergistic interaction of various factors is discussed.     

Dependence of the degree of synergism in the simultaneous action of UV light and hyperthermia on yeast cells on the intensity of the UV light

In experiments with wild-type diploid yeast cells of Saccharomyces cerevisiae it was shown that the definite temperature interval revealed the synergistic effect under simultaneous action of UV radiation and hyperthermia. The correlation between the degree of synergistic interaction and UV light intensity and irradiation temperature was estimated: the temperature interval synergistically enhancing the UV light effect was shifted towards higher temperatures as the UV light intensity was increasing, the optimal temperature to achieve the most synergistic effect existing for every intensity examined.     

Theoretical considerations on potentiation in drug interaction

To account for some of the more important aspects of drug interaction we shall consider a model which can also account for certain general properties of the action of a single drug. A simple model in which there may be enzymatic detoxification of a drug is studied theoretically. The relation between time for appearance of an effect due to the drug and the size of the dose is found to contain the same parameters as the relation between the effectiveness of paired doses and the interval of time between doses. A similar situation holds when the drug is given at a constant rate. When two drugs are administered together, their effect will depend on the manner of interaction, how much of each drug is given, which is given first, and on the interval of time between each administration. A number of plausible types of interaction is considered theoretically in terms of the model, analytical expressions being given for a number of cases. The interaction may be synergistic or antagonistic. In the former case the potentiation may be more than or less than additive depending on the order of delivery and on the time between injections. Methods for the estimation of the parameters from data are discussed.     

An analysis of the interaction of a platinum complex and radiation with CHO cells using the molecular theory of cell survival.

A mathematical analysis is developed from the concepts of the molecular theory of cell survival to explain the cytotoxic action of a platinum complex on CHO cells and its synergistic interaction with radiation. In the analysis, it is assumed that both inter- and intra-strand cross-links induced by the Pt complex in the DNA contribute to cell killing and that the synergistic effect arises from the interaction between an intra-strand cross-link and a radiation-induced single-strand break on complementary strands of the DNA. The analysis is shown to be compatible with experimental results. Further, a mechanistic model is developed in an attempt to explain in more detail the processes which appear to be involved in the expression of the cytological damage.     

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.     

Recovery of yeast cells after exposure to ionizing radiation and hyperthermia

Quantitative regularities of recovery of wild-type diploid yeast cells irradiated with gamma-rays (60Co) simultaneously with exposure to high temperatures were studied. It was shown that in conditions of such a combined action the constant of recovery did not depend on the temperature at which the irradiation was carried out. However, with an increase of acting temperature an augmentation in the portion of irreversible component was registered. The analysis of cell inactivation revealed that the augmentation of the irreversible component was accompanied by a continuous increase of cell killing without any postirradiation division after which cells are incapable of recovery. The reproductive death was mainly exerted after ionizing radiation applied alone while in conditions of simultaneous thermoradiation action the interphase killing (cell death without division) predominated. It is concluded on this base that the mechanism of synergistic interaction of ionizing radiation and hyperthermia may be related with cardinal change in mechanisms of cell killing.     

Mathematical modeling of the synergistic effects of sequential thermoradiation action on mammalian cells

In order to estimate the dependence of the synergistic enhancement ratio on the damage level induced by ionizing radiation and hyperthermia, data obtained by other authors for mammalian cells treated with sequential thermoradiation were used. The experimental results were described and interpreted by means of the mathematical model of synergism, according to which synergism is determined by additional lethal damage arising from the interaction of nonlethal sublesions induced by individual damaging agents.     

Effect of elevated temperatures on the radiation sensitivity of yeast cells of different species

Summary The influence of hyperthermia on the survival of irradiated yeast cells of different species has been studied. The experiments reported in the paper have shown: (1) simultaneous action of ionizing radiation and high temperatures appeared to increase the radiation response by a factor of approximately 2.7 for diploid and only by a factor of 1.5 for haploid cells of wild-type; (2) the combined action of high temperature and ionizing radiation had no synergistic effect for rad51 mutant diploid yeast cells; (3) heating before or after irradiation did not alter the radiation response of yeast cells; (4) enhancement of yeast cell sensitivity by simultaneous action of hyperthermia and²³⁹Pu--particles was negligible; (5) the magnitude and the rate of liquid holding recovery is lowered with increasing of irradiation temperature. On this basis, it was concluded that possible mechanism for thermal sensitization of yeast cells may involve the reduced capacity of cells to recover damages resulted from the combined action of both modalities.     

Baclofen and NOS inhibitors interact to evoke synergistic hypothermia in rats

Our laboratory recently demonstrated that a drug combination of baclofen and L-NAME, a nonspecific nitric oxide synthase (NOS) inhibitor, evokes synergistic hypothermia in rats. These data are the first demonstration of synergy between a GABA agonist and NOS inhibitor. While the hypothermic synergy suggests a role for NOS in baclofen pharmacology, it is unclear whether the super-additive hypothermia is specific for baclofen and L-NAME or extends to drug combinations of baclofen and other NOS inhibitors. The site of action (central or peripheral) and isoforms of NOS that mediate the synergy are also unknown. Here, we confirm the hypothermic synergy with additional data and discuss potential mechanisms of the drug interaction. Baclofen (2.5, 3.5, 5 and 7.5 mg/kg, i.p.) was administered to rats by itself or with 7-nitroindazole (7-NI), a neuronal NOS inhibitor. 7-NI (10 mg/kg, i.p.) did not affect body temperature. For combined administration, 7-NI (10 mg/kg, i.p.) increased the relative potency of baclofen (F=18.9, P<0.05). The present data validate the hypothermic synergy caused by the drug combination of baclofen and L-NAME and implicate nNOS in the synergy. In a context broader than thermoregulation, NO production and transmission may play an important role in baclofen pharmacology.     

Stimulation of DNA synthesis in Jurkat cells by synergistic action between adenine and guanine nucleotides.

P2-purinoceptor agonists stimulated the DNA synthesis of Jurkat cells via a pathway independent of cAMP and intracellular free calcium. The response was greatly enhanced by the synergistic action between adenine and guanine nucleotides, suggesting that binding sites of these nucleotides are different from each other, and the proliferation is stimulated by a novel interaction between adenine and guanine nucleotide receptors. The stimulatory effects of P2-agonists on proliferation was completely abolished by cholera toxin and attenuated by pertussis toxin, which suggests that substrates for cholera toxin and pertussis toxin are involved in the proliferative pathways associated with P2-purinoceptors.     

Multiple cytokine interactions regulate Ly-6E antigen expression: cooperative Ly-6E induction by IFNs, TNF, and IL-1 in a T cell lymphoma and in its induction-deficient variants.

The cell surface Ly-6E antigen, known to play a role in T cell activation, is up-regulated by IFNs. In the present study, we investigated the possible interactions between IFNs and other cytokines in this regulation. As a model system, we used the YAC T cell lymphoma, in which Ly-6E is normally absent but can be highly induced both at the mRNA and surface protein levels by IFN-gamma or IFN-alpha/beta. The combination of the two IFNs was found to result in markedly synergistic Ly-6E induction in this cell line. Moreover, mutants of YAC cells were isolated that did not respond to the Ly-6E-inducing action of IFN-gamma or IFN-alpha/beta alone but did respond to their combination. Such a synergistic interaction is consistent with the notion that the two IFN types utilize different intracellular mechanisms to induce Ly-6E expression. Ly-6E induction mediated by IFN-gamma or IFN-alpha/beta was also enhanced by cotreatment with TNF-alpha or IL-1 alpha, which by themselves had no detectable Ly-6E-inducing effect. These two cytokines similarly synergized with IFNs to trigger a response in several Ly-6E-induction-deficient mutants. However, their action could be dissociated in one mutant (B54) where the response to IFN-alpha/beta was enhanced by TNF-alpha, but not by IL-1 alpha. Altogether, these data indicate that Ly-6E antigen expression is regulated by the interaction of several inflammatory cytokines, which may provide a mechanism for the local modulation of T cell activation. The YAC cell mutants described here should facilitate further analysis of the molecular bases of Ly-6E regulation.     

Tumorigenesis in transgenic mice: identification and characterization of synergizing oncogenes.

Transgenic mice carrying oncogenes present a useful model with which to assess the tissue-specific action of oncogenes. These mice are usually predisposed to a specific type of neoplastic growth. The tumors that arise are usually monoclonal in origin and become only apparent after a variable latency period, suggesting that additional events are required for tumor formation. Identification of these additional events is highly relevant: it might give access to the genes that can synergize with a preselected oncogene in tumorigenesis and could facilitate the identification of the biochemical pathways in which these genes act. Retroviruses can be instrumental in identifying cooperating oncogenes. Proto-oncogene activation or tumor suppressor gene inactivation by insertional mutagenesis is an important mechanism by which the non-acute transforming retroviruses can induce tumors in several species. Owing to the sequence tag provided by the provirus, the relevant proto-oncogene can be directly identified by cloning of the DNA flanking the proviral insertion site. We have exploited this potential of retroviruses by infecting E mu-pim-1 and E mu-myc transgenic mice, which are predisposed to lymphomagenesis, with Moloney murine leukemia virus (MuLV). A strong acceleration of tumor induction ensued upon infection of these mice with MuLV. More importantly, it allowed us to identify a number of additional common insertion sites marking both previously known as well as new (putative) oncogenes. In a significant portion of the tumors more than one oncogene was found to be activated, indicating that within this system the synergistic effect of at least three genes can be established.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hsp90 regulates the activity of wild type p53 under physiological and elevated temperatures

The activity and structural integrity of the tumor suppressor protein p53 is of crucial importance for the prevention of cancer. p53 is a conformational flexible and labile protein, in which structured and unstructured regions function in a synergistic manner. The molecular chaperone Hsp90 is known to bind to mutant and wild type p53 in vivo. Using highly purified proteins we analyzed the interaction and the binding sites between both proteins in detail. Our results demonstrate that Hsp90 binds to a folded, native-like conformation of p53 in vitro with micromolar affinity. Specifically, the DNA-binding domain of p53 and the middle and carboxy-terminal domains of Hsp90 are responsible for this interaction, which is essential to stabilize p53 at physiological temperatures and to prevent it from irreversible thermal inactivation. Our results are in agreement with a model in which Hsp90 is required to maintain the folded, active state of p53 by a reversible interaction, thus introducing an additional level of regulation.     

Mediator-assisted laccase-catalyzed oxidation of 4-hydroxybiphenyl

The kinetics of oxidation of 4-hydroxybiphenyl (4-HBP) catalyzed by laccase from Polyporus pinsitus was studied in the presence of methyl syringate (MS), which acts as an electron-transfer mediator. Measurements were performed in 0.05 M acetate buffer, pH 5.5, in the presence of 4-HBP, MS, and laccase. It is shown that the oxidation rate of the lowly reactive substrate 4-HBP significantly increases during synergistic action of the highly reactive substrate MS. Bimolecular kinetic constants of interaction between the oxidized form of laccase and MS, the former and 4-HBP, and the oxidized form of MS and 4-HBP were calculated. A kinetic scheme of the synergistic substrate action is suggested; based on this scheme, the dependence of the initial rate on reagent concentration is derived. Analyzing experimental data, we obtained kinetic constants close to those obtained by modeling the processes.     

Multi-Objective Evolutionary Optimization of Biological Pest Control with Impulsive Dynamics in Soybean Crops

The biological pest control in agriculture, an environment-friendly practice, maintains the density of pests below an economic injury level by releasing a suitable quantity of their natural enemies. This work proposes a multi-objective numerical solution to biological pest control for soybean crops, considering both the cost of application of the control action and the cost of economic damages. The system model is nonlinear with impulsive control dynamics, in order to cope more effectively with the actual control action to be applied, which should be performed in a finite number of discrete time instants. The dynamic optimization problem is solved using the NSGA-II, a fast and trustworthy multi-objective genetic algorithm. The results suggest a dual pest control policy, in which the relative price of control action versus the associated additional harvest yield determines the usage of either a low control action strategy or a higher one.