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Biomedical subjects

M Astor

Publications and source records attributed to M Astor.

At least 19 recordsLinked to original sources
PubMed1997

Statistical framework for ultrasonic spectral parameter imaging.

This study examines the statistics of ultrasonic spectral parameter images that are being used to evaluate tissue microstructure in several organs. The parameters are derived from sliding-window spectrum analysis of radiofrequency echo signals. Calibrated spectra are expressed in dB and analyzed with linear regression procedures to compute spectral slope, intercept and midband fit, which is directly related to integrated backscatter. Local values of each parameter are quantitatively depicted in gray-scale cross-sectional images to determine tissue type, response to therapy and physical scatterer properties. In this report, we treat the statistics of each type of parameter image for statistically homogeneous scatterers. Probability density functions are derived for each parameter, and theoretical results are compared with corresponding histograms clinically measured in homogeneous tissue segments in the liver and prostate. Excellent agreement was found between theoretical density functions and data histograms for homogeneous tissue segments. Departures from theory are observed in heterogeneous tissue segments. The results demonstrate how the statistics of each spectral parameter and integrated backscatter are related to system and analysis parameters. These results are now being used to guide the design of system and analysis parameters, to improve assays of tissue heterogeneity and to evaluate the precision of estimating features associated with effective scatterer sizes and concentrations.

Carcinoma↗
PubMed1992

Biological intercomparisons of neutron beams used for radiotherapy generated by p(+)-->Be in hospital-based cyclotrons.

The new generation of hospital-based neutron therapy facilities involve cyclotrons using protons on beryllium. The spectrum of neutrons produced includes a large and variable proportion of low-energy neutrons that are poorly penetrating but biologically effective. Cells cultured in vitro were used to compare the three US facilities at Seattle, M.D. Anderson and UCLA, together with the UK facility at Clatterbridge. Cyclotrons were compared within a given experiment on the same day using cells from a common suspension. Among the three US facilities, the relative potency factor at a depth of 25 mm differs by about 11%, with Seattle the least and UCLA the most biologically effective. Clatterbridge was compared directly with M.D. Anderson and found to be less effective by about 5%; it has a slightly lower biological effectiveness than any of the US facilities. There is evidence for an increased biological effectiveness in the build-up region, which reduces the effective skin sparing potential. There is not much difference in build-up between the three US facilities. Using the proton-on-beryllium neutron production process results in a wide spectrum of neutrons with a large but variable low-energy component. The biological effectiveness of the beam depends on target design and thickness as well as the design of the collimating system. Consequently the biological effectiveness of neutron beams generated by this process must be assessed on an individual basis. It cannot be assumed that because cyclotrons have similar accelerating energies that the relative biological effectiveness will be the same.

Animals↗
PubMed1989

Changes in biological effectiveness of the neutron beam at Clatterbridge (62 MeV p on Be) measured with cells in vitro.

Chinese hamster V79 cells have been used to assess changes in RBE of the p(62)Be neutron beam at the Clatterbridge Hospital with depth in a phantom and with use of a hydrogenous filter. The cells were exposed at depths of 2 and 12 cm and at a depth of 2 cm with a hydrogenous filter. Two groups of experimenters each conducted two experiments. The ratios of relative biological effectiveness (RBE) at a depth of 12 cm to that at 2 cm were found by the two groups to be 0.99 +/- 0.04 and 0.96 +/- 0.02 (standard errors). The effect of a polythene filter 4.5 cm thick was measured at a depth of 2 cm and the ratio of RBE with and without the filter was found by both groups to be 0.99 +/- 0.02. All the experiments suggest that there may be small effects of beam hardening by depth and filtration but these results are in marked contrast with those obtained using an in vivo system.

Animals↗
PubMed1988

Basic radiobiology.

Experimental studies of the biological effects of radiation were started soon after the discoveries of x-rays in 1895, but there is still much that is not known. This article includes some research objectives that are essentially pragmatic in nature, intended to support and improve the current practice of radiotherapy, but the central thrust is the understanding of the mechanisms involved in the biological effects of radiation at the cellular and molecular levels. The article was written by a consortium of scientists and suffers inevitably from the drawback that writing styles are inconsistent, and coverage is not uniform. However, it benefits from the enormous advantage that it reflects the accumulated wisdom and judgment of more than a dozen scientists who, in their own areas of expertise, are recognized as being at the cutting edge of radiation research. The niceties of style and syntax are sacrificed in favor of the quality of the science and the maturity of judgment. The study of DNA damage as a mechanism for cell injury in early- and late-responding tissues, as well as a comparison of DNA damage that leads to lethality, as opposed to transformation and mutagenesis, are key items. The study of cell lethality with cells in culture led to the identification of repair, both sublethal and potentially lethal, as well as the dose-rate effect, and has had a considerable impact on radiotherapy. Future studies should focus on understanding the factors that determine radiosensitivity/radioresistance. A variety of approaches are available, including the study of genetically deficient cell lines from cancer-prone individuals. A parallel approach is the application of the techniques of molecular biology to clone the repair genes in mammalian cells, and to understand genetic defects that alter gene regulation, or to regulate biochemical factors in the cell. Substantial progress has been made in developing in vitro assays for mutagenesis, particularly using hybrids of rodent and human cells. Better methods are needed to study the effects of mutation on gene expression, and sensitive systems are needed that can detect low doses of radiation. Assays of oncogenic transformation, the in vitro counterpart of carcinogenesis, have been used to investigate the oncogenic potential of various types of radiation and chemotherapy agents. Key topics in future will include the investigation of supra-additivity between different agents, the identification and characterization of oncogenes that may be activated by radiation, the development of quantitative assays based on human cells, and further studies involving cell-to-cell communication.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Relationship between thiol depletion and chemosensitization in a transplantable murine bladder tumor.

The effect of pretreating the C3H/He mouse MBT-2 tumor with diethyl maleate (DEM), buthionine-S R-sulfoximine (BSO), or misonidazole (MISO) before administration of cyclophosphamide (CTX) was studied with the use of tumor volume-doubling time delay as an endpoint. The kinetics of glutathione (GSH) depletion and regeneration in the tumor and in the host liver were determined after treatment with the thiol-depleting agents. CTX was administered at appropriate time points. MISO was the most effective chemosensitizer at a time point at which tumor GSH content was 80-85% of the control value. Both BSO and DEM were chemosensitizers in relation to the degree they had reduced tumor GSH levels. This chemosensitization was significant at 50% GSH reduction. By combining MISO and BSO at doses lower than previously used for each agent alone, highly effective sensitization of subsequent CTX was obtained.

Animals↗
PubMed1984

Factors involved in depletion of glutathione from A549 human lung carcinoma cells: implications for radiotherapy.

We have measured the rate of GSH resynthesis in plateau phase cultures of A549 human lung carcinoma cells subjected to a fresh medium change. Buthionine sulfoximine (BSO) blocks this resynthesis. Diethyl maleate (DEM) causes a decrease in accumulation of GSH. If DEM is added concurrently with BSO there is a rapid decline in GSH that is maximal in the presence of 0.5 mM DEM. GSH depletion rapidly occurs when BSO is added to log phase cultures which initially are higher in GSH content. Twenty-four hr treatment of A549 cells with BSO results in cells that are more radiosensitive in air and show a slight hypoxic radiation response. A 2 hr treatment with either 0.25 mM or 0.5 mM DEM results in some hypoxic sensitization and little increase in the aerobic radiation response. The 24 hr BSO + 2 hr DEM treatment sensitizes hypoxic cells to a greater degree than either agent alone but does not increase the aerobic response more than is seen with BSO alone. Cells treated simultaneously with BSO + DEM show little increase in the hypoxic radiation response, compared to DEM alone, but are more sensitive under aerobic conditions. Decreased cell survival for aerobically irradiated log phase A549 cells occurs within minutes after addition of a mixture of BSO + DEM. The decreased cell survival following aerobic irradiation, after prolonged treatment with BSO or acute exposure to BSO + DEM, may be in part due to inhibition of glutathione peroxidases. For example, glutathione-S-transferase, known to have glutathione peroxidase activity (non-selenium), is nearly completely inhibited by the BSO treatments. In addition, cellular capacity to react with peroxide (glutathione peroxidase, selenium containing) was also inhibited. We suggest that the enhanced aerobic radiation response is related to an inability of GSH depleted cells to inactivate either peroxy radicals or hydroperoxides that may be produced during irradiation of BSO treated cells. Furthermore, enhancement of the aerobic radiation response may be useful in vivo if normal tissue responses are not also increased.

Buthionine Sulfoximine↗
PubMed1982

Newly synthesized hypoxia-mediated drugs as radiosensitizers and cytotoxic agents.

Chinese hamster cells in culture were used to compare the radiosensitizing efficiency and cytotoxicity of misonidazole with several 2, 4 and 5 substituted nitroimidazoles. The two substituted compounds (SR 2508 and SR 2555) are similar to misonidazole in radiosensitizing effectiveness, but are significantly less toxic to hypoxic cells. This reduced cytotoxicity may result from either slower drug penetration or slower removal of non-protein sulfhydryl compounds (NPSH). The compound MJL-1-191-VII (a 4-nitroimidazole) is a much more effective radiosensitizer than would be predicted from its electron affinity. It appears to sensitize by two mechanisms, the first resulting from its electron affinity and the second as consequence of its rapid removal of endogeneous cellular NPSH; which are naturally occurring radioprotective substances.

Animals↗
PubMed1982

Radiobiological studies with therapeutic neutron beams generated by p+ leads to Be or d+ leads to Be.

Mammalian cells cultured in vitro were used to study the radiobiological characteristics of neutron beams generated by 43 MeV protons on beryllium or 25 MeV deutrons on beryllium. For an unfiltered beam of neutrons generated by 43 MeV p+ leads to Be the relative biological effectiveness was found to be 8-12% higher at a depth of 2 cm than at a depth of 12 cm due to the presence of a large component of low-energy neutrons. The addition of a hydrogenous filter 4 cm thick preferentially removed the low-energy neutrons from the beam and, as a result, the neutron RBE was independent of depth. There was no significant difference in the oxygen enhancement ratio between the filtered neutrons produced by 43 Mev p+ leads to Be and neutrons produced by 25 MeV d+ leads to Be; for both beams the OER value was about 1.6.

Animals↗
PubMed1979

Misonidazole and MTDQ in combination: cytotoxic and radiosensitizing properties in hypoxic mammalian cells.

A combination of misonidazole and MTDQ (6,6'-methylene-bis-2,2,4 trimethyl-1,2-dihydroquinoline) has been tested for its radiation-sensitizing properties and cytotoxicity, using Chinese hamster V79 cells cultured in vitro. Both compounds sensitize hypoxic cells to the effects of X-rays, and when used in combination their sensitizing properties are additive. By contrast, the presence of MTDQ completely inhibits the cytotoxicity that misonidazole exhibits towards hypoxic cells. These experiments shed some light on the mechanism of action of electron-affinic hypoxic cell sensitizers, and the combination of radiosensitizers suggested may have an application in human cancer radiotherapy by eliminating the neurotoxicity experienced by patients receiving misonidazole during radiotherapy.

Animals↗
PubMed1977

Cytotoxicity of Ro-07-0582; enhancement by hyperthermia and protection by cysteamine.

The selective cytotoxicity which Ro-07-0582 exhibits towards hypoxic cells is strongly temperature-dependent. This cytotoxicity is reduced by the radical scavenger cysteamine, suggesting that nitro radicals or nitroso intermediates are involved in cell killing by the drug. Chromosome aberrations are not induced by Ro-07-0582 even when the surviving fraction is reduced to 0-01.

Cell Survival↗
PubMedDate not supplied

The enhanced sensitivity of mammalian cells to killing by X rays after prolonged exposure to several nitroimidazoles.

Electron affinic compounds, such as misonidazole, preferentially sensitize hypoxic cells to killing by X rays, and are also preferentially cytotoxic to cells deficient in oxygen. Prolonged exposure of cells to misonidazole prior to irradiation results in an increased radiosensitization. This is expressed as the Extra Enhancement Ratio (EER), defined as the ratio of the doses delivered immediately after the addition of the sensitizer or after prolonged incubation, that produce a given biological effect. Chinese hamster V79 cells have been used to investigate this prolonged incubation effect for a variety of 2-nitroimidazoles including misonidazole, desmethylmisonidazole and SR-2508 and as well as two ortho-substituted-4-nitroimidazoles with a bromine or sulfonamide group substituted in the 5-position. A considerable variation was observed in the magnitude of the Extra Enhancement Ratio (EER) produced by pre-incubation with different compounds at concentrations that produce the same sensitizing effect. There is a good correlation between the EER and the measured rate at which the various sensitizers deplete cells of non-protein sulfhydryl compounds. There is also a good correlation between the EER and the fraction of cells killed by the pre-incubation period in the drug.

Animals↗