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C R Geard

Publications and source records attributed to C R Geard.

At least 55 records · Page 3Linked to original sources
PubMed1991

Evidence of genotoxic damage in human cataractous lenses.

Lens epithelial fragments (tags) recovered from individuals during routine cataract extraction have been assessed for cellular changes reflective of genotoxic damage. A high percentage of tags exhibited a population of micronucleated and polyploid cells. The presence and number of micronuclei (MN) in the epithelia of cataract patients appears to be independent of age and sex. However, a large number of MN in the epithelial cells of some individuals strongly suggests a history of compromised genomic integrity. While the study was not designed to define the role of DNA damage in the development of cataracts or to monitor human populations at risk of exposure to exogenous mutagens/cataractogens, the potential of the methodology to address each is demonstrated.

Adult↗
PubMed1991

Oncogenic transformation following sequential irradiations with monoenergetic neutrons and X rays.

Mouse C3H 10T1/2 cells were exposed sequentially to low doses (0.1 and 0.3 Gy) of monoenergetic neutrons (0.35, 0.45, 5.9, and 13.7 MeV) and 250-kVp X rays (1 and 3 Gy). The incidences of oncogenic transformation in the cells exposed to neutrons followed by X rays indicated that the effects of the individual radiations were simply additive. This supports the contention that risks associated with the two different radiation modalities may be considered to be additive.

Animals↗
PubMed1990

Radioresponse of human astrocytic tumors across grade as a function of acute and chronic irradiation.

Astrocytomas make up the largest group of primary brain tumors of glial origin. Long term survival is rare with high grade tumors (grades 3 and 4), which recur despite subtotal resection, chemotherapy, and aggressive postoperative radiation therapy. In contrast, the 5-year survival for low grade astrocytomas (grades 1 and 2) following subtotal resection and postoperative radiotherapy approaches 50%. Variable sensitivity across grade may contribute to the difference in the behavior of these tumors. To investigate this possibility, the radioresponse of human glial tumors across grade as a function of the dose rate of irradiation was studied. Cell lines derived from a low grade astrocytoma (grade 1) and two high grade astrocytomas (grades 3 and 4) were established in culture. Clonal survival was determined following irradiation of the three cell lines with Cesium 137 gamma rays at high dose rate, 78 Gy/hr, and at low dose rate, range 14 cGy to 79 cGy/hr. The low grade astrocytoma was found to be more radiosensitive than either of the high grade tumors. The alpha/beta (Gy-1/Gy-2) values (linear quadratic model) were 0.35/0.082 for the grade 1 line and 0.20/0.036 and 0.30/0.045 for the grade 3 and 4, respectively. D0 (cGy) values (single-hit multi-target model) were 99, 144, and 117 for grades 1, 3, and 4, respectively. A dose rate effect was present for all three tumor lines irradiated from 14 cGy/hr to 78 Gy/hr. An inverse dose rate effect was also noted at 37 cGy/hr for each of the astrocytic lines. These findings may be useful in the development of strategies to treat astrocytic brain tumors which use high and/or low dose rate irradiation.

Astrocytoma↗
PubMed1990

Micronuclei and clonogenicity following low- and high-dose-rate gamma irradiation of normal human fibroblasts.

Plateau-phase human fibroblasts were irradiated at either low dose rate (approximately 0.6 Gy/h) or high dose rate (78 Gy/h) with gamma rays and then released from contact inhibition. The frequency of cells containing micronuclei monitored at daily intervals showed that induction was dependent on both dose and dose rate with a peak incidence at 3 days postirradiation. Cumulative frequency distributions indicated a reduction by a factor of 4 when the dose was delivered chronically as opposed to acutely. Distributions also suggested that micronuclei-containing cells persist over days, while the dose responses (different by a factor of 2.8) for both high and low dose rate indicated a plateau, particularly following higher doses at low dose rate. Data were not consistent with this response being due to cell cycle delay. Delayed plating resulted in both a reduced incidence of cells with micronuclei and enhanced survival following high- but not low-dose-rate irradiation, with the response being complete by 6 h. Cell surviving fraction and the fraction of cells with micronuclei were negatively correlated, but the relationships were different between the high- and low-dose-rate irradiations. This divergence mitigates against using low-dose-rate responsiveness of the short-term micronucleus assay as an indicator of the initial slope of the acute dose-rate survival curve.

Cell Survival↗
PubMed1989

Neutron-energy-dependent oncogenic transformation of C3H 10T1/2 mouse cells.

The relative biological effectiveness (RBE) of a range of neutron energies relative to 250-kVp X rays has been determined for oncogenic transformation and cell survival in the mouse C3H 10T 1/2 cell line. Monoenergetic neutrons at 0.23, 0.35, 0.45, 0.70, 0.96, 1.96, 5.90, and 13.7 MeV were generated at the Radiological Research Accelerator Facility of the Radiological Research Laboratories, Columbia University, and were used to irradiate asynchronous cells at low absorbed doses from 0.05 to 1.47 Gy. X irradiations covered the range 0.5 to 8 Gy. Over the more than 2-year period of this study, the 31 experiments provided comprehensive information, indicating minimal variability in control material, assuring the validity of comparisons over time. For both survival and transformation, a curvilinear dose response for X rays was contrasted with linear or nearly linear dose responses for the various neutron energies. RBE increased as dose decreased for both end points. Maximal RBE values for transformation ranged from 13 for cells exposed to 5.9-MeV neutrons to 35 for 0.35-MeV neutrons. This study clearly shows that over the range of neutron energies typically seen by nuclear power plant workers and individuals exposed to the atomic bombs in Japan, a wide range of RBE values needs to be considered when evaluating the neutron component of the effective dose. These results are in concordance with the recent proposals in ICRU 40 both to change upward and to vary the quality factor for neutron irradiations.

Animals↗
PubMed1988

Oncogenic transformation by fractionated doses of neutrons.

Oncogenic transformation was assayed after C3H 10T1/2 cells were irradiated with monoenergetic neutrons; cells were exposed to 0.23-, 0.35-, 0.45-, 5.9-, and 13.7-MeV neutrons given singly or in five equal fractions over 8 h. At the biologically effective neutron energy of 0.45 MeV, enhancement of transformation was evident with some small fractionated doses (below 1 Gy). When transformation was examined as a function of neutron energy at 0.5 Gy, enhancement was seen for cells exposed to three of the five energies (0.35, 0.45, and 5.9 MeV). Enhancement was greatest for cells irradiated with 5.9-MeV neutrons. Of the neutron energies examined, 5.9-MeV neutrons had the lowest dose-averaged lineal energy and linear energy transfer. This suggests that enhancement of transformation by fractionated low doses of neutrons may be radiation-quality dependent.

Animals↗
PubMed1987

The lens and cataract: clastogenic responses in epithelial cells of the organ-cultured rat lens.

The epithelial cells of the vertebrate lens have an unique character and a probable involvement in cataract formation, which could be initiated by exogenous stimuli. Individual rat lenses were organ-cultured, and the effects of mitomycin C and gamma rays on sister chromatid exchanges (SCE), chromosomal aberrations, and cellular kinetics assessed in cells from the epithelial monolayer. SCE showed about a 5.5-fold increase over the mitomycin C dose range (0, 17, 83, 170 nM), while chromosomal aberrations increased 38-fold. In cells from untreated lenses, SCE were 1,600 times more frequent than aberrations and at a level consistent with in vivo assessments in other cell types. Gamma rays (up to 4 Gy) had a greater inhibiting effect on cellular progression, while 17 nM mitomycin C and 1 Gy induced similar clastogenic responses. This first demonstration of such changes in lens epithelial cells expands on the cell types available for monitoring potential mutagen-carcinogens. Additionally chromosomal changes resulting from lens cellular challenge could be the basis of later cytopathological changes in the lens, of which cataract is the primary concern to humans. Potential cataractogens warrant monitoring, and the study outlined may aid in this endeavor, as well as contributing to an understanding of cataract etiology.

Animals↗
PubMed1987

Cell survival and plating efficiency.

The question of whether cellular radiation sensitivity is independent or related to plating efficiency (PE) is addressed. Three different cell lines, one human and mortal (AG 1522), one rodent and immortal (CHO AA8), and one rodent and mortal (C3H 10T1/2), were investigated. The first two showed a strong correlation between radiation sensitivity and PE, even when, for the mortal cells, the effect of passage number was factored out.

Animals↗
PubMed1986

Glutathione levels and cytotoxicity of a thiol activated alkylating agent in human and mouse cells.

The effects of cellular GSH levels on the cytotoxicity of MNNG and mitomycin C were examined in normal and BSO treated mouse C3H10T1/2 cells. MNNG was less cytotoxic in the GSH depleted cells (less than 10% of normal) whereas the cytotoxicity of mitomycin C was not influenced by thiol status. This is compatible with the alkylating agent MNNG requiring thiols for activation to the methylating electrophile. Conversely, thiols have little if any effect in modulating the activity of mitomycin C. When naturally thiol deficient human fibroblasts were compared with BSO treated fibroblasts depleted to a similar GSH level (less than 10% of normal), only the BSO depleted cells were less effected by MNNG. The GSH deficient cells showed the same MNNG dose response as normal human fibroblasts. These studies indicate that a naturally acquired thiol status and an equivalent induced thiol status need not behave the same and this needs consideration when evaluating the role of thiols in influencing cellular response to chemotherapeutic agents.

Animals↗
PubMed1986

Low dose-rate effects of cesium-137 and iodine-125 on cell survival, cell progression, and chromosomal alterations.

Chinese hamster ovary (CHO-AA8) cells in exponential growth were exposed to graded doses of radiation from iodine-125 (I-125) or cesium-137 (Cs-137) at various low dose rates, then monitored for cell number and clonogenic integrity. Cellular kinetics and the induction of sister chromatid exchanges and chromosomal aberrations were evaluated in cells after irradiation. Dose rates within the range 3-23 cGy/h had little effect on these fast growing cells but there was significant cell killing at dose rates of 33-70 cGy/h. The relative biological effectiveness (RBE) values for I-125 relative to Cs-137, calculated from the cell growth curves and the percentage of plating efficiencies of irradiated cells as a fraction of control, were 1.28 and 1.5., respectively, and did not vary over the dose-rate range from 3 to 70 cGy/h. The percentage of mitoses with chromosomal aberrations increased as a function of dose, but showed little if any change with dose rate. Cells passing through two cell cycles after irradiation also showed dose-dependent increases in the frequency of sister chromatid exchanges. That is, viable cells continue to show the effects of low dose-rate irradiation at the DNA level long after irradiation is concluded. Frequencies of cells in mitosis (mitotic index) and of cells incorporating bromodeoxyuridine (BrdU) (cycling S phase cells) indicated that low dose-rate I-125 irradiation produced a much more profound delay than low dose-rate of Cs-137 irradiation. This more pronounced inhibition may play a significant role in enhancing the effect of low dose rate I-125 in a clinical situation.

Animals↗
PubMed1985

In vitro assessment of the oncogenic potential of nitroimidazole radiosensitizers.

Two hypoxic cell radiosensitizers, RSU-1069 and Ro-03-8799 were investigated for their in vitro cytotoxicity and ability to induce oncogenic transformation and sister chromatid exchanges in the C3H 10T1/2 cell system. Their effects were then compared to those of the clinically used sensitizer misonidazole. Equitoxic doses of Ro-03-8799 and RSU-1069 were approximately 3-fold and 150-fold less than misonidazole, respectively, with both agents exhibiting dose and contact time dependence for cell killing. Both sensitizers appeared no more oncogenic than misonidazole when administered at equitoxic dosages. At doses of equivalent sensitizing efficiencies relative to misonidazole, RSU-1069, but not Ro-03-8799, induced significantly higher transformation incidence. In conjunction with gamma-irradiation, both Ro-03-8799 and misonidazole induced an additive transformation response. Preliminary studies also indicate that RSU-1069, at a concentration of 0.03 mM, induced significantly higher sister chromatid exchanges (SCE) per chromosome than either Ro-03-8799 or misonidazole at concentrations 30-fold higher. Although several earlier studies have indicated that RSU-1069 may be more efficient than misonidazole as an hypoxic cell sensitizer, the present findings suggest that it may also carry a higher risk of inducing tumors by itself at clinically relevant concentrations.

Animals↗
PubMed1985

Correlation of in vitro genotoxicity and oncogenicity induced by radiation and asbestos fibres.

The in vitro cytotoxicity and oncogenic potential of both native and acid leached asbestos fibres were studied using the C3H 10T1/2 cell model. Both native and leached fibres induced a dose-dependent toxicity. At high fibre concentrations, acid leached fibres were significantly less toxic than their untreated counterparts. While asbestos fibres alone do not induce oncogenic transformation at the concentration examined, it was found that both leached and native fibres substantially enhanced the oncogenicity of gamma-irradiation in a more than additive fashion. Although no significant chromosomal aberrations or sister chromatid exchanges (SCE) were found in asbestos treated cultures, a significantly higher number of SCEs was observed in cells treated with both asbestos and radiation compared to cells receiving radiation alone. The results suggest that the enhancement in radiation induced oncogenicity by asbestos fibres may be attributed to the mere physical presence of the fibres rather than any chemical contaminants the fibres may contain. Furthermore, the carcinogenicity of asbestos may be unrelated to genotoxicity.

Animals↗
PubMed1985

Charged particle cytogenetics: effects of LET, fluence, and particle separation on chromosome aberrations.

Induced rearrangements of chromosomes, disrupting the orderly sequence and/or separation of the genetic material, are responsible for a significant proportion of cellular lethality, genetic mutation, and, as has become increasingly apparent in recent years, human cancer. The quantitative observation of chromosomal aberrations induced by ionizing radiations led early to the realization that as linear energy transfer (LET) increased, curvilinear dose responses became increasingly linear. Those few studies that examined aberrations as a function of LET found that the optimally effective LET was about 100 keV per micrometer, results consistent with those observed for other end points. The majority of chromosomal aberrations originate from molecular interaction between pairs of lesions (misrepair), with differences in sensitivity to aberration induction through the cell cycle. In Chinese hamster V-79 cells for all LET values studied, aberrations are most frequent in G2, then G1, then S phase of the cell cycle. The variation in sensitivity through the cell cycle changes from a factor of about 5 for 10 keV/micron particles to about 3 for 80 keV/micron particles. In the G2 phase a curvilinear dose response (G1 and S being linear) is found for all LETs occurring at fluences where there are substantial distances (greater than or equal to 3 micron) between particles. It is possible that for this one phase of the cell cycle a saturation of repair capabilities occurs as a function of both fluence and LET. When cells were irradiated with associated charged particles (molecular ions) it was found that even when two particles were separated by distances of less than 100 nm their effect was much less than one particle of twice the LET (the equivalent of 0 distance separation). This implies that the vast majority of molecular interactions which result in chromosomal aberrations occur as a consequence of interaction between damaged sites formed only a few nanometers from each other. It is clear that an analysis of chromosomal aberrations produced by charged particles can provide considerable insight into basic radiobiological mechanisms and into the organization of the mammalian genome.

Alpha Particles↗
PubMed1984

Effects of cellular non-protein sulfhydryl depletion in radiation induced oncogenic transformation and genotoxicity in mouse C3H 10T1/2 cells.

A study was made of the effects of cellular non-protein sulfhydryl (NPSH) depletion on cytotoxicity, cell cycle kinetics, oncogenic transformation and sister chromatid exchange (SCE) in C3H 10T1/2 cells. Using DL-Buthionine S-R-Sulfoximine (BSO) at a concentration of 0.05 mM to deplete thiols, it was found spectrophotometrically that less than 5% of control NPSH level remained in the cells after 24-hour treatment under aerated conditions. Such NPSH depleted cells, when subject to a 3 Gy gamma-ray treatment, were found to have no radiosensitizing response either in terms of cell survival or oncogenic transformation. In addition, decreased levels of NPSH had no effect on spontaneous or radiation-induced SCE nor were cell cycle kinetics additionally altered. Therefore, the inability of NPSH depletion to alter gamma-ray induced cellular transformation was unrelated to any possible effect of BSO on the cell cycle. These results suggest that, while endogenous NPSH depletion has been considered to play an important role for most radiosensitizers in clinical or preclinical use, such depletion may result in little or no additional oncogenic or genotoxic effects on aerated normal tissues.

Aerobiosis↗
PubMed1984

Paraquat and radiation effects on mouse C3H 10T1/2 cells.

The dipyridilium compound, paraquat, has been used in conjunction with mouse C3H 10T1/2 cells to determine if this superoxide (O2-) generating agent acts to oncogenically transform, chromosomally alter or influence cytokinetics or cellular survival. Paraquat alone is a cytotoxic agent and is additionally a weak radiosensitizer. A 0.1 mM 24 hour treatment results in about 30% cell survival and enhances the cell killing effects of 137Cs gamma rays by a factor of about 1.2. The drug appears to function lethally by initiating an interphase cell death, and additionally slows the movement of cycling cells through the cell cycle. It is a poor inducer of SCE's and combined effects with radiation are strictly additive. Paraquat oncogenically transforms cells but not in a dose-dependent manner, yet combined treatments with 3 Gy result in transformation frequencies greater than expected for additive effects. Depending on the endpoint examined, which may be related to the degree of nuclear involvement, paraquat either acts additively (SCE's) or with greater than an additive effect (cell survival and oncogenic transformation).

Animals↗
PubMed1984

Magnetic resonance and ionizing radiation: a comparative evaluation in vitro of oncogenic and genotoxic potential.

This paper describes experiments designed to investigate possible biological hazards associated with magnetic resonance (MR) imaging. Mouse C3H 10T1/2 cells were exposed to a powerful magnetic field (up to 2.7 T) for periods up to 17 hours together with pulsed field gradients and radio-frequency excitation and compared with untreated controls and cells exposed to gamma rays (0.3 to 0.4 Gy). Several biological endpoints were studied. In the case of oncogenic transformation, no significant difference could be demonstrated between controls and either the gamma-irradiated or MR-exposed cells. When mitotic cells were examined for chromosomal alterations, the frequencies of both chromosomal aberrations per cell and sister chromatid exchanges per chromosome were significantly enhanced over control levels after ionizing radiation exposures but were similar to control (or less) after MR exposures. These studies confirm the known deleterious effects of ionizing radiation (even at low doses) for chromosomal damage, if not for oncogenic transformation, yet show that MR exposures even of long duration (up to 17 hours) at high field strengths (up to 2.7 T) do not result in effects greater than 0.3 Gy of gamma rays. Negative results do not conclusively rule out a health risk; however, the data clearly mitigate against an association between exposure to MR imaging modalities and both carcinogenic and genotoxic effects.

Animals↗