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Biomedical subjects

C R Geard

Publications and source records attributed to C R Geard.

At least 73 records · Page 4Linked to original sources
PubMed1983

Chromosomal aberrations and delays in cell progression induced by X-rays in Tradescantia clone 02 meristems.

In root meristems of Tradescantia clone 02 (developed by Sparrow and his colleagues for mutation studies), X-rays interfere with the progression of cells through the cell cycle and induce chromosomal aberrations in a dose-dependent manner consistent with linear-quadratic kinetics. Sequential mitotic cell accumulations after irradiation indicate that sensitivity to aberration induction is probably greatest in cells from late S to early G2, with chromatid interchanges the most frequent aberration type and all aberrations consistent with initiation from the interaction between two lesions. The ratio of the coefficients in the linear (alpha) and the quadratic (beta) terms (alpha/beta) is equal to the dose average of specific energy produced by individual particles in the site where interaction takes place. The ratio alpha/beta for chromosomal aberrations is similar to that previously found for X-ray-induced mutation in Tradescantia stamen hairs, supporting the proposal that radiation-induced mutational events are due to chromosomal aberrations with interaction distances of about 1 micron. Abrahamson and co-workers have noted that both alpha/beta ratios appear to be related to nuclear target size and are similar for chromosomal and mutational endpoints in the same organism. These findings support this concept; however, it is apparent that any situation which diminishes yield at high doses (eg, mitotic delay) will primarily affect the beta component, resulting in low assessments of interaction site diameters.

Cell Cycle↗
PubMed1982

A comparison of the cytological effects of three hypoxic cell radiosensitizers.

Misonidazole has entered Phase III clinical trials as a hypoxic cell radiosensitizer. Neurotoxocity is the major dose-limiting factor and has prompted the development of two further compounds with reduced lipophilicity and shorter half-life in vivo. Aside from the short-term problem of neurotoxocity, other potential long-term consequences should be considered. Such is the purpose of this investigation where the cytological effects of three radiosensitizers upon oxic and hypoxic Chinese hamster V-79 cells have been examined. Two newer compounds, desmethylmisonidazole and Stanford Research compound 2508, were compared with their clinically used predecessor, misonidazole. Under aerated conditions, cell killing was increased with SR-2508 in a concentration and time dependent manner, so as to exceed by more than three times the level produced by the other two drugs at 5 mM for 72 hours. Cell progression into mitosis was also markedly reduced by as much as 1/10,000 of control values. However, as the three compounds induced similar frequencies of sister chromatid exchange (SCE) and chromosome aberration, the enhanced cytotoxic effect of SR-2508 appears to be mediated via an interphase rather than a post-mitotic cell death. Cells were made hypoxic and treated with the three drugs for 4 hr, then mitoses sequentially collected for 16 hr. The three compounds produced similar levels of cell killing, slowing of cell cycle progression, SCE's and chromosome aberrations, with cycle-specific effect on S and G-1 phase cells for SCE induction. These results indicate that desmethylmisonidazole and misonidazole have similar cytotoxic and clastogenic properties under oxic and hypoxic conditions. SR-2508 is relatively more toxic to aerated cells and may deserve close clinical observation for toxicity to normal tissues; further, all three agents may enhance DNA damage and mutagenesis in tissues that are normally hypoxic.

Animals↗
PubMed1981

Antipain and radiation effects on oncogenic transformation and sister chromatid exchanges in Syrian hamster embryo and mouse C3H/10T1/2 cells.

Depending on its time of addition to Syrian hamster embryo or mouse C3H 10T1/2 cells the protease inhibitor antipain (AP) can enhance, or reduce, radiation induced-oncogenic transformations. These opposing influences are not paralleled by changes in sister chromatid exchanges in either cell system. A 24 h treatment with 10 microM AP prior to, and during irradiation, with removal 10 min after irradiation results in greater than a two-fold increase in transformants. Conversely, a 24 h treatment beginning 10 min after irradiation results in about a two-fold decrease in transformants. The utility of AP as an agent for the reduction of tumorigenesis is brought into question, since quite short temporal differences in application can result in near five-fold differences in the frequencies of oncogenic transformations.

Animals↗
PubMed1981

Modification of sister chromatid exchanges and radiation-induced transformation in rodent cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and two retinoids.

Modification of sister chromatid exchanges and radiation-induced transformation in mouse C3H/10T 1/2 and Syrian hamster embryo cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and two retinoids, the trimethylmethoxyphenyl analog of N-ethyl retinamide and beta-all-trans-retinoic acid, has been studied. 12-O-tetradecanoylphorbol-13-acetate alone enhances, and retinoids alone reduce radiation-induced transformation. When both compounds were present, the retinoids not only reduced the oncogenic effects of radiation but completely eliminated the promoting effects of 12-O-tetradecanoylphorbol-13-acetate. These results were not paralleled by changes in sister chromatid exchange frequencies, indicating that, while sister chromatid exchanges may be useful as indicators of primary carcinogen mutagens, they may have little utility when secondary agents after the response of cells to a primary initiator.

Animals↗
PubMed1980

Effects of 1.9 MeV monoenergetic neutrons on Vicia faba chromosomes: microdosimetric considerations.

Aerated Vicia faba root meristems were irradiated with 1.9 MeV monoenergetic neutrons. This source of neutrons optimally provides one class of particles (recoil protons) with ranges able to traverse cell nuclei at moderate to high-LET. The volumes of the Vicia faba nuclei were log-normally distributed with a mean of 1100 micrometer3. The yield of chromatid-type aberrations was linear against absorbed dose and near-constant over 5 collection periods (2-12 h), after irradiation. Energy deposition events (recoil protons) determined by microdosimetry were related to cytological changes with the finding that 19% of incident recoil protons initiate visible changes in Vicia faba chromosomes. It is probable that a substantial fraction of recoil proton track length and deposited energy is in insensitive (non-DNA containing) portions of the nuclear volume.

Cell Nucleus↗
PubMed1980

On the mechanics of chromosomal aberrations: a study with single and multiple spatially-associated protons.

A unique radiation configuration, triads of protons, where mean separation between protons was controlled to be about 0.2 microns, has been used to irradiate Chinese hamster V79 cells. These triads of accelerated particles were more effective at producing chromosomal aberrations than randomly incident particles. Cells were irradiated with either single or three associated protons, with each proton depositing energy intracellularly at an LET of about 30 keV per micron. The associated protons were produced from accelerated molecular ions (H3+) that dissociated into atomic ions in a 6 mu Mylar foil on which the cells were growing, becoming triads of particles separated by a mean of about 0.2 microns in the cell nuclei. Chromosomal aberrations were scored from cells accumulated with colcemid over hourly intervals after irradiation. Those cells closest to mitosis (late G2) were the most sensitive to radiation, while overall "triple" protons were 52% more effective than single protons in producing aberrations. Only 10% of particles incident in nuclei resulted in an effect for the most sensitive period (late G2) dropping to 2% for the least sensitive period (early S--late G1). The frequencies of chromatid deletions declined dramatically with time post-irradiation, with isochromatid deletions less so and the frequencies of chromatid interchanges comparatively unchanged. Chromatid deletions and isochromatid deletions were often subtantially increased after "triple" proton irradiation, with the frequencies of chromatid interchanges less effected. This implies that both chromatid and isochromatid deletions can readily result from interactions between pairs of induced lesions about 0.2 microns apart. Achromatic lesions (gaps) were numerically equivalent after both irradiations implying a single lesion production mode. Results are compatible with there being a substantial short range component of interaction (less than 0.1 microns) between damaged sites, with a long range component of interaction extending to a few tenths of a micrometer.

Animals↗
PubMed1980

Effects of long contact times of misonidazole on attached Chinese hamster V79 cells.

The 2-nitroimidazole misonidazole, an hypoxic cell radiation sensitizer, has been shown to be cytotoxic to attached oxic Chinese hamster V79 cells after high doses and long contact times. This killing effect is enhanced if BrdU is incorporated into chromosomes. It was found that misonidazole slows cell progression through the cell cycle and that those cells that move into mitosis carry very few chromosomal aberrations suggesting that the majority of cells are dying in interphase. The level of induced SCEs both in 2nd and 3rd division cells was comparatively slight; being always less than twice the control level although there was an indication of an increased incidence with dose. Since human exposure to misonidazole will only be at low concentrations, these results imply that misonidazole is a comparatively safe agent, particularly when its effect are contrasted with those of other chemotherapeutic agents.

Animals↗
PubMed1978

Cytological effects of 1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol (misonidazole) on hypoxic mammalian cells in vitro.

Hypoxic Chinese hamster V-79 cells were examined for light-microscope morphology, progression through the cell cycle, chromosomal aberrations, and viability, after incubation with the 2-nitroimidazole, misonidazole [1-(2-nitro-1-imidazolyl)-3 methoxy-2-propanol]. Cytological examination of cells up to 42 hr after incubation with the drug at 37 degrees indicated that increasing contact time and increasing drug concentrations interfered with cell attachment and progressively slowed cell progression through the cell cycle. Forty-two hr after a 5.5-hr treatment with 5 mM misonidazole, the majority of cells contained heteropyknotic nuclei, whereas less than 3% had progressed into mitosis. Of the few cells that reached mitosis by 42 hr, the level of chromosomal aberrations was 6 times that due to hypoxia alone. However, the majority of metaphases (70%) were unaltered; thus about 2% of the treated cell population passed into mitosis unaltered. After a 5.5-hr incubation with 5 mM misonidazole, 98% of the cells also had lost their ability to produce clones. It is suggested that the cytotoxic effect of this drug on hypoxic cells is that the cytotoxic effect of this drug on hypoxic cells is largely mediated via an interphase cell death, with a minor effect due to chromosome aberrations and cell death from genetic inequality of progeny cells. The ability of misonidazole to kill hypoxic, noncycline cells, which may limit the curability of some tumors with conventional X-rays or chemotherapy agents, makes it of considerable potential interest.

Anaerobiosis↗
PubMed1977

Microdosimetry and chromosome aberrations: effects of 230 keV neutrons on Vicia faba chromosomes.

Physical energy deposition events have been related to sub-nuclear cytological events (chromosomal changes) in metaphases sequentially accumulated from the latter part of the cell cycle of Vicia faba. 230 keV neutrons produce about 0.4 recoil protons per late interphase nucleus per rad with the majority of protons traveling 1 to 2 microns from their origin, depositing energy at around 90 keV per micron. The frequency of induced abberrations is basically linear with dose, though varying through consecutive cell sampling periods because of differential induced mitotic delay. Distributions of chromosomal aberrations and total cytological events are overdispersed in relation to the Poisson distribution indicating that some proton recoils produce multiple events. When gaps and aberrations within chromosomes and multiple aberrations between chromosomes, are considered as discrete events, distributions follow Poisson expectations. About 40% of proton recoils result in observable cytological change. The highly energetic proton recoils (approximately 90 keV per micron) which can induce multiple events are the ones most likely to produce effects which result in cell death. The sphere of influence of the proton recoils is probably adequately estimated from their range (approximately 1 to 2 micron) since it seems compatible with the spatial proximity of the initial components of the resultant chromosome aberrations.

Chromosome Aberrations↗