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Biomedical subjects

E J Hall

Publications and source records attributed to E J Hall.

At least 181 records · Page 10Linked to original sources
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

The oncogenic potential of a combination of hyperthermia and chemotherapy agents.

The modulating effect of 43 degrees C hyperthermia on the induction of oncogenic transformation by the antineoplastic agents, actinomycin D, mitomycin C, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) was examined using the C3H 10T1/2 cell line. For any given level of cytotoxicity, cells exposed to the three chemotherapy agents at 37 degrees C showed similar frequencies of transformation. Transformation frequencies induced by all three drugs were reduced by hyperthermia. The reduction was most pronounced for cells exposed to BCNU, and to a lesser extent, by cells exposed to actinomycin D and mitomycin C. The modulating effects of heat on drug-induced transformation incidence appeared to be independent of whether application of heat and drug was concurrent or sequential.

Animals↗
PubMed1988

Oncogenic transformation by charged particles of defined LET.

Neoplastic transformation incidence and cytotoxicity were scored in the C3H/10T1/2 cell system following irradiation with charged particles of defined linear energy transfer (LET) produced at the Radiological Research Accelerator Facility of Columbia University. Cells cultured in monolayers, attached to thin Mylar sheets, were irradiated with accelerated protons, deuterons or helium-3 ions, and the results compared with X-rays. Defined LET values obtained by using the track segment mode, ranged from 10 to 120 keV/microns. For X-rays, and for the charged particles of lower LET, the dose-response curves for cell survival have a marked initial shoulder. With increasing LET, there is a progressive decrease in the size of the shoulder and for the highest LETs, survival curves approximate an exponential function of dose. The transformation incidence, likewise, showed a direct correlation to LET over the dose range examined. The efficiencies of transformation, however, appeared to approach a plateau between 80 and 120 keV/micron. Transformation data were analyzed using a linear-quadratic function of dose for the transformation probability. This latter quantity, when analyzed using microdosimetric consideration, suggests that the target volume for this end point is of the order of micrometer.

Animals↗
PubMed1988

Mutation induction by charged particles of defined linear energy transfer.

The mutagenic potential of charged particles of defined linear energy transfer (LET) was assessed using the hypoxanthine-guanine phosphoribosyl transferase locus (HGPRT) in primary human fibroblasts. Exponentially growing cultures of early passaged fibroblasts were grown as monolayers on thin mylar sheets and were irradiated with accelerated protons, deuterons or helium-3 ions. The mutation rates were compared with those generated by 137Cs gamma-rays. LET values for charged particles accelerated at the Radiological Research Accelerator Facility, using the track segment mode, ranged from 10 to 150 keV/micron. After irradiation, cells were trypsinized, subcultured and assayed for both cytotoxicity and 6-thioguanine resistance. For gamma-rays, and for the charged particles of lower LET, the dose-response curves for cell survival were characterized by a marked initial shoulder, but approximated to an exponential function of dose for higher LETs. Mutation frequencies, likewise, showed a direct correlation to LET over the dose range examined. Relative biological effectiveness (RBE) for mutagenesis, based on the initial slopes of the dose-response curves, ranged from 1.30 for 10 keV/micron protons to 9.40 for 150 keV/micron helium-3 ions. Results of the present studies indicate that high-LET radiations, apart from being efficient inducers of cell lethality, are even more efficient in mutation induction as compared to low-LET ionizing radiation. These data are consistent with results previously obtained with both rodent and human fibroblast cell lines.

Cell Survival↗
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↗
PubMed1988

Mutation induction and relative biological effectiveness of neutrons in mammalian cells. Experimental observations.

The induction of mutation by graded doses of monoenergetic neutrons was examined using the human-hamster hybrid cell system. The AL cells, formed by fusion of human fibroblasts with the gly- A mutant of the Chinese hamster ovary cells, contain the standard set of hamster chromosomes plus a single human chromosome, number 11. These cells contain specific human cell surface antigens that render them sensitive to killing by specific antisera in the presence of complement. Mutant AL cells that have lost the surface markers, however, would survive and give rise to scorable colonies. The cells were irradiated with neutrons produced at the Radiological Research Accelerator Facility of Columbia University. Doses corresponding to low, moderate, and high cytotoxicities and in energies ranging from 0.33 to 14 MeV were used. Neutrons induced a dose-dependent cytotoxicity and mutation frequency in the AL cells. Over the range of doses examined, it was found that the mutagenesis induced by neutrons was energy-dependent and the frequencies were a curvilinear function of dose for both the a1 and a2 antigenic loci examined. In comparison to gamma rays, the relative biological effectiveness (RBE) for cell lethality at the 10% survival level ranged from 5.2 for 0.33 MeV to 1.8 for 14 MeV neutrons. The RBE for mutation induction at the a1 locus, however, ranged from 30 for 0.33 MeV to 4.2 for 14 MeV neutrons at or around the lowest levels of effect examined. Results of the present study demonstrated that neutrons, when measured under conditions which permit detection of a spectrum of gene and chromosomal mutations, in fact, are more efficient mutagens than previously thought.

Animals↗
PubMed1988

Low-dose rate irradiation.

There are a number of rather obvious conclusions from these experimental data that have implications in clinical radiotherapy: (1) Survival curves for cells of human origin, in general, have a smaller initial shoulder and exhibit greater sensitivity to ionizing radiation than cells of rodent origin. (2) Nevertheless, the response of human cells to gamma-rays, in a fractionated or low-dose schedule, is dominated by repair. (3) Radiosensitivity, as well as the repair of sublethal damage as evidenced by the dose rate effect, is very similar for a range of normal human cells, including skin and lung fibroblasts, as well as endothelial cells from umbilical cord veins. (4) Human tumor cells are much more variable than normal cells in radiosensitivity, and in the repair of sublethal damage, evident in the dose rate effect. Some show a smaller, and some show a larger dose rate effect than normal cells. (5) Consequently, the use of a large number of fractions, as for example in hyperfractionation regimens, is contraindicated in those tumors that show repair factors larger than for normal tissues; though of course it is a substantial advantage in other cases.

DNA Repair↗
PubMed1988

Radiation response characteristics of human cells in vitro.

Improvements in tissue culture techniques and growth media have made it possible to culture a range of cells of human origin, both normal and malignant. The most recent addition to the list are endothelial cells from umbilical cord veins. Interesting results in radiosensitivity studies of these human cells have been obtained, some of which may have implications in radiation therapy. (i) Repair of potentially lethal damage (PLDR) has been observed in all cell lines investigated; cells of normal origin repair PLD at least as well as malignant cells, which makes clinical trials of PLDR inhibitors of doubtful usefulness. (ii) No apparent correlation can be made between the extent of PLDR and the traditional radioresponsiveness of a particular tumor type. Indeed, if anything, it could appear to have an inverse correlation since the most resistant tumor cells show the smallest amount of PLD repair. (iii) Dose-rate effects appear to be better predictors of radiosensitivity than PLDR capacity. (iv) Sublethal damage repair, manifest by a dose-rate effect, has also been observed in all human cell lines tested. Cells of normal tissue origin, including fibroblasts and endothelial cells, exhibit a dose-rate effect that is intermediate between that for cells from traditionally resistant tumors (melanoma and osteosarcoma) and cells from more sensitive tumors (neuroblastoma and breast).

Cell Line↗
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

Radiosensitivity and sublethal damage repair in human umbilical cord vein endothelial cells.

The assessment of the comparative radiosensitivity of different parenchymal cells is potentially of great importance in clinical radiotherapy. Previous studies from various laboratories using vessel regeneration techniques have demonstrated that endothelial cells are quite radioresistant, having a Do in excess of 250 rads. The present studies were undertaken to investigate the radiosensitivity of human endothelial cells obtained from umbilical cord veins (HEC) using "colony formation" as an endpoint, and to evaluate their ability to repair sublethal radiation damage (SLD). The endothelial origin of the cells in the surviving colonies was demonstrated by their positive staining for factor VIII antigen. The survival curve for HEC has a Do of about 165 rads, with a moderate initial shoulder. Dose fractionation studies demonstrate a moderate capability to repair SLD, comparable to other human cells studied including fibroblasts and other normal diploid cells in vitro. These studies indicate that HEC, being a terminally differentiated cell type with various differentiated markers, may prove useful in radiobiological and radiocarcinogenesis studies.

Cell Survival↗
PubMed1987

Potentially lethal damage repair in human cells.

Potentially lethal damage repair (PLDR) in human cells was investigated by delayed plating experiments with three malignant tumor cell lines (breast, colon and neuroblastoma) and two normal diploid lines (lung fibroblasts) in exponential and plateau phases. All cell lines demonstrated PLDR which was considerably higher for all the cell lines in plateau phase compared to log phase. At survival levels of 0.01, the two fibroblast lines had recovery ratios of 3.8 and 4.0 for 6 h delayed plating in plateau phase. The malignant lines showed recovery ratios of 5.7 (neuroblastoma), 3.2 (breast carcinoma) and 2.4 (colon carcinoma). The data were fitted to the linear quadratic equation and in addition, a repair factor was developed to compare survival for immediate and delayed plating: S(D) = exp[-gamma (alpha D + beta D2)] where gamma = 1 for immediate plating. Previously published data on human tumor and normal lines were also fitted to this equation. In all instances the three parameter equation (alpha, beta, gamma) allowed a good fit of the survival data for immediate and delayed plating. By using the same alpha, beta for the zero hour and 6 h survival curves, the gamma factor allows a much more useful method of comparing PLDR among different cell lines. The gamma factor for the two lung fibroblast lines were 0.70 and 0.71 while skin fibroblasts also had a 0.71 factor. The six malignant lines ranged from 0.62 to 0.93 with all but the neuroblastoma line having a higher factor (and therefore decreased PLDR capacity) than the normal lines. No correlation between PLDR and in vitro radiosensitivity or clinical radiosensitivity of the tumor type was found.

Cell Line↗
PubMed1987

Dose-rate effects in normal and malignant cells of human origin.

Human cell lines derived from normal tissue and malignant tumours were irradiated in plateau phase under acute (81 Gy/h) or protracted (0.1-0.7 Gy/h) exposure to determine initial survival curve slopes, assess sublethal damage repair (SLDR) capability, and establish differences in survival due to SLDR over a range of dose rates. No correlation was found between clinical resistance of the tumor types and initial slope or survival at 2 Gy. Sublethal damage repair was assessed by comparing survival curves for acute and continuous irradiation. All cell lines showed significant SLDR, with the more clinically resistant tumour types demonstrating the best recovery rates. The survival data also demonstrated little difference in cell killing over the 0.1-0.7 Gy/h range. Using a modified linear-quadratic model with provisions for SLDR, it was found that for these cell lines the repair half-time was less than 1 h, with no significant change in the amount of recovery from sublethal damage at dose rates below 1 Gy/h.

Cell Line↗
PubMed1986

Biochemistry of reduction of nitro heterocycles.

Misonidazole is a metabolically active drug. Its addition to cells causes an immediate alteration in cellular electron transfer pathways. Under aerobic conditions the metabolic alterations can result in futile cycling with electron transfer to oxygen and production of peroxide. Thiol levels are extremely important in protecting the cell against the peroxide formation and potentially hazardous conditions for hydroxyl radical production. Nevertheless such electron shunting out of cellular metabolism will result in alterations in pentose cycle, glycolysis and cellular capacity to reduce metabolites to essential intermediates needed in DNA metabolism (i.e. deoxyribonucleotides). Glutathione must be depleted to very low levels before toxic effects of misonidazole and other nitro compounds are manifested in cell death via peroxidative damage. Under hypoxic conditions misonidazole also diverts the pentose cycle via its own reduction; however, unlike the aerobic conditions, there are a number of reductive intermediates produced that react with non-protein thiols such as GSH as well as protein thiols. The reaction with protein thiols results in the inhibition of glycolysis and other as yet undetermined enzyme systems. The consequences of the hypoxic pretreatment of cells with nitro compounds are increased vulnerability to radiation and chemotherapeutic drugs such as L-PAM, cis-platinum and bleomycin. The role that altered enzyme activity has in the cellular response to misonidazole and chemotherapeutic agents remains to be determined. It is also clear that the GSH depleted state not only makes cells more vulnerable to oxidative stress but also to hypoxic intermediates produced by the reduction of misonidazole beyond the one electron stage. The relevancy of the present work to the proposed use of thiol depletion in vivo to enhance the radiation or chemotherapeutic response of tumor tissue lies with the following considerations. Apparently, spontaneous peroxidative damage to normal tissue such as liver can occur with GSH depletion to 10-20% of control and with other normal tissue when GSH reaches 50% of control. This situation can obviously become more critical if peroxide producing drugs are administered. The only advantage to such combined drug treatments would lie in the possibility that tumors vary in their catalase and peroxidase activity and consequently may be more vulnerable to oxidative stress (cf. review by Meister. Our tumor model, the A549 human lung carcinoma cell in vitro, appears to be an exception because it has catalase, peroxidase and a high content of GSH.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗